leukaemia research reports

• B-cell lymphoblastic leukemia
• T-cell lymphoblastic leukemia
• Acute promyelocytic leukemia
• NPM1-mutated acute myeloid leukemia
• Large granular lymphocytic leukemia
• Hairy cell leukemia
• Chronic myeloid leukemia
• Chronic myelomonocytic leukemia
• Childhood leukemia

About our Research Grants

• Our approach
• Grant programs
• Current research

Funding Opportunities

• Eligibility + guidelines + application

Completed research + results

• About Clinical Trials
• How Do Clinical Trials Work?
• Clinical Trial Myths and Facts
• Clinical Trials Questions
• Are Clinical Trials Safe?
• Financial and Insurance Considerations
• Diversity in Clinical Trials
• Online Clinical Trial Finder

Information + resources

• Newly diagnosed
• Other helpful resources

Education programs

• Leukemia Q+A
• New + Emerging Treatments

Support services

• Peer support
• Financial assistance

Ways to Give

• Monthly gifts
• Tribute gifts
• Employer matching
• Gifts of stock
• Donor-advised funds
• Legacy giving
• Charity Miles and Fundraising
• ABC7 Gibbons 5k Run + 3k Walk
• Join an Event

Information

Committees + volunteers.

• Medical Advisory Board
• Affiliate Board
• Patient Advisory Committee
• Volunteer chapters
• Board of Directors

Current Research

Robert Bowman, PhD

University of Pennsylvania, Perelman School of Medicine

Grant awarded: 2023 Disease: Leukemia (AML) Research focus: Cell Biology

Yu-Chiao Chiu, PhD

University of Pittsburgh

Grant awarded: 2023 Disease: Leukemia (AML) Research focus: Treatment

Marta Derecka, PhD

St. Jude Children's Research Hospital, Inc.

Grant awarded: 2023 Disease: Myelofibrosis Research focus: Cell Biology

Francesca Ferraro, MD, PhD

Washington University in St. Louis

Grant awarded: 2023 Disease: Acute myeloid leukemia (AML) Research focus: Relapse prevention

Zhaohui Gu, PhD

Beckman Research Institute of the City of Hope

Grant awarded: 2023 Disease: Acute lymphoblastic leukemia (ALL) Research focus: Relapse prevention

Xue Han, PhD,

The Ohio State University

Tania Jain, PhD

Johns Hopkins University School of Medicine

Grant awarded: 2023 Disease: Myeloproliferative neoplasms, acute myeloid leukemia (AML) Research focus: Treatment

Qingfei Jiang, PhD

University of California, San Diego

Grant awarded: 2023 Disease: Acute lymphocytic leukemia (ALL) Research focus: Treatment

Theodoros Karantanos, MD, PhD

Grant awarded: 2023 Disease: Acute myeloid leukemia (AML) Research focus: Cell Biology

Linde Miles, PhD

Cincinnati Children's Hospital Medical Center

Joshua Riback, PhD

Baylor College of Medicine

Reona Sakemura, MD

Mayo Clinic Rochester

Grant awarded: 2023 Disease: Acute Lymphoblastic Leukemia (ALL) Research focus: Treatment

Christian Schuerch, PhD

University of Tübingen

Grant awarded: 2023 Disease: Acute myeloid leukemia (AML) Research focus: Relapse Prevention

Alan Shih, MD, PhD

Icahn School of Medicine at Mount Sinai

Srividya Swaminathan, PhD

Daniel Utzschneider, PhD

Peter Doherty Institute at the University of Melbourne

Grant awarded: 2023 Disease: Chronic Lymphocytic Leukemia (CLL) Research focus: Treatment

Timothy Barrow, PhD

University of Essex

Grant awarded: 2022 Disease: Leukemia (CLL) Research focus: Relapse prevention (minimal residual disease)

Lina Benajiba, MD, PhD

INSERM Institute of Health and Medical Research

Grant awarded: 2022 Disease: Leukemia (AML) Research focus: Cancer cell biology (microenvironment)

Christian Hurtz, PhD

Temple University

Grant awarded: 2022 Disease: Leukemia (ALL) Research focus: Treatment (targeted therapy)

Yoon-A Kang, PhD

Washington University in St.Louis

Grant awarded: 2022 Disease: Leukemia (MPNs) Research focus: Causes/risk factors (MPNs)

Anja Karlstaedt, MD, PhD

Cedars-Sinai Medical Center

David Kurtz, MD, PhD

Stanford University

Grant awarded: 2022 Disease: Multiple myeloma Research focus: Treatment (immunotherapy)

Laura Mondragon Martinez, PhD

Josep Carreras Leukaemia Research Institute

Grant awarded: 2022 Disease: Lymphoma (non-Hodgkin) Research focus: Treatment (immunotherapy)

Rui Su, PhD

Grant awarded: 2022 Disease: Leukemia (AML) Research focus: Cancer cell biology (leukemia stem cells)

To learn about research projects, supported by the Leukemia Research Foundation in previous years, and their results, click here .

Advertisement

Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

• T-Cell and Other Lymphoproliferative Malignancies (J Zain, Section Editor)
• Published: 15 February 2020
• Volume 15 , pages 103–112, ( 2020 )

Cite this article

• HeeJin Cheon 1 , 2 , 3 ,
• Karolina H. Dziewulska 1 , 4   na1 ,
• Katharine B. Moosic 1 , 4   na1 ,
• Kristine C. Olson 1 ,
• Alejandro A. Gru 4 ,
• David J. Feith 1 &
• Thomas P. Loughran Jr. 1  

3101 Accesses

37 Citations

1 Altmetric

Explore all metrics

Purpose of Review

The past decade in LGL leukemia research has seen increased pairing of clinical data with molecular markers, shedding new insights on LGL leukemia pathogenesis and heterogeneity. This review summarizes the current standard of care of LGL leukemia, updates from clinical trials, and our congruent improved understanding of LGL pathogenesis.

Recent Findings

Various clinical reports have identified associations between stem, bone marrow, and solid organ transplants and incidence of LGL leukemia. There is also a potential for underdiagnosis of LGL leukemia within the rheumatoid arthritis patient population, emphasizing our need for continued study. Preliminary results from the BNZ-1 clinical trial, which targets IL-15 along with IL-2 and IL-9 signaling pathways, show some evidence of clinical response.

With advances in our understanding of LGL pathogenesis from both the bench and the clinic, exciting avenues for investigations lie ahead for LGL leukemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

Novel Therapeutic Targets in Acute Myeloid Leukemia (AML)

Michael Wysota, Marina Konopleva & Shane Mitchell

International Consensus Classification of acute lymphoblastic leukemia/lymphoma

Amy S. Duffield, Charles G. Mullighan & Michael J. Borowitz

A genetic profiling guideline to support diagnosis and clinical management of lymphomas

Margarita Sánchez-Beato, Miriam Méndez, … Mariano Provencio

Papers of particular interest, published recently, have been highlighted as: • Of importance

Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129:1082–94.

Article   CAS   PubMed   Google Scholar  

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Loughran TP, Kadin ME, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, et al. Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. Ann Intern Med. 1985;102:169–75.

Article   PubMed   Google Scholar  

Jerez A, Clemente MJ, Makishima H, Koskela H, Leblanc F, Peng Ng K, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood. 2012;120:3048–57.

Rajala HLM, Eldfors S, Kuusanmäki H, van Adrichem A, Olson T, Lagström S, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 2013;121:4541–50.

Koskela HLM, Eldfors S, Ellonen P, van Adrichem A, Kuusanmäki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366:1905–13.

Loughran TP. Clonal diseases of large granular lymphocytes. Blood. 1993;82:1–14.

Dinmohamed AG, Brink M, Visser O, Jongen-Lavrencic M. Population-based analyses among 184 patients diagnosed with large granular lymphocyte leukemia in the Netherlands between 2001 and 2013. Leukemia. 2016;30:1449–51.

Shah MV, Hook CC, Call TG, Go RS. A population-based study of large granular lymphocyte leukemia. Blood Cancer J. 2016;6:e455.

Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95:1534–41.

Suzuki R, Suzumiya J, Nakamura S, Aoki S, Notoya A, Ozaki S, et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004;18:763–70.

Moignet A, Lamy T. Latest advances in the diagnosis and treatment of large granular lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2018;38:616–25.

Lamy T, Loughran TP. How I treat LGL leukemia. Blood. 2011;117:2764–74.

Bockorny B, Dasanu CA. Autoimmune manifestations in large granular lymphocyte leukemia. Clin Lymphoma Myeloma Leuk. 2012;12:400–5.

Liu X, Loughran TP. The spectrum of large granular lymphocyte leukemia and Felty’s syndrome. Curr Opin Hematol. 2011;18:254–9.

Qiu Z-Y, Qin R, Tian G-Y, Wang Y, Zhang Y-Q. Pathophysiologic mechanisms and management of large granular lymphocytic leukemia associated pure red cell aplasia. Onco Targets Ther. 2019;12:8229–40.

Kawakami T, Sekiguchi N, Kobayashi J, Imi T, Matsuda K, Yamane T, et al. Frequent STAT3 mutations in CD8+ T cells from patients with pure red cell aplasia. Blood Adv. 2018;2:2704–12.

Gentile TC, Uner AH, Hutchison RE, Wright J, Ben-Ezra J, Russell EC, et al. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood. 1994;84:2315–21.

Morice WG, Jevremovic D, Hanson CA. The expression of the novel cytotoxic protein granzyme M by large granular lymphocytic leukaemias of both T-cell and NK-cell lineage: an unexpected finding with implications regarding the pathobiology of these disorders. Br J Haematol. 2007;137:237–9.

Loughran TP, Zickl L, Olson TL, et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015;29:886–94.

Loughran TP, Kidd PG, Starkebaum G. Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood. 1994;84:2164–70.

• Lamy T, Pastoret C, Houot R, et al. Prospective, multicentric phase II randomized trial comparing the efficacy of methotrexate or cyclophosphamide in large granular lymphocytic leukemia: a french national study. Report on the interim analysis. Blood. 2019;134:1545–5 This is the current ongoing prospective study comparing the efficacy of methotrexate or cyclophosphamide in LGL leukemia .

Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem Drugs. 1991;42:781–95.

CAS   PubMed   Google Scholar  

Smith RE, Bryant J, De Cillis A, Anderson S, National Surgical Adjuvant Breast and Bowel Project Experience. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21:1195–204.

Moignet A, Hasanali Z, Zambello R, Pavan L, Bareau B, Tournilhac O, et al. Cyclophosphamide as a first-line therapy in LGL leukemia. Leukemia. 2014;28:1134–6.

Graham RM. Cyclosporine: mechanisms of action and toxicity. Cleve Clin J Med. 1994;61:308–13.

Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, et al. Network model of survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci U S A. 2008;105:16308–13.

Sun H, Wei S, Yang L. Dysfunction of immune system in the development of large granular lymphocyte leukemia. Hematology Am Soc Hematol Educ Program. 2019;24:139–47.

CAS   Google Scholar  

Kallemeijn MJ, de Ridder D, Schilperoord-Vermeulen J, van der Klift MY, Sandberg Y, van Dongen JJM, et al. Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia. PLoS One. 2017;12:e0175670.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Leblanc F, Zhang D, Liu X, Loughran TP. Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. Future Oncol. 2012;8:787–801.

Viny AD, Maciejewski JP. High rate of both hematopoietic and solid tumors associated with large granular lymphocyte leukemia. Leuk Lymphoma. 2015;56:503–4.

Nyland SB, Feith DJ, Poss M, Olson TL, Krissinger DJ, Poiesz BJ, et al. Retroviral sero-reactivity in LGL leukaemia patients and family members. Br J Haematol. 2019. https://doi.org/10.1111/bjh.16223 .

Wlodarski MW, Nearman Z, Jankowska A, Babel N, Powers J, Leahy P, et al. Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia. J Leukoc Biol. 2008;83:589–601.

Viny AD, Lichtin A, Pohlman B, Loughran T, Maciejewski J. Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leuk Lymphoma. 2008;49:932–8.

Skarbnik APZ, Portell CA, Maciejewski JP, et al. Association of large granular lymphocytic leukemia (LGL) with B-cell lymphoproliferative disorders. Blood. 2013;122:1387–7.

Starkebaum G, Loughran TP, Kalyanaraman VS, Kadin ME, Kidd PG, Singer JW, et al. Serum reactivity to human T-cell leukaemia/lymphoma virus type I proteins in patients with large granular lymphocytic leukaemia. Lancet. 1987;1:596–9.

Loughran T, Coyle T, Sherman M, Starkebaum G, Ehrlich G, Ruscetti F, Poiesz B Detection of human T-cell leukemia/lymphoma virus, type 11, in a patient with large granular lymphocyte leukemia.

Pulik M, Lionnet F, Genet P, Petitdidier C, Jary L, Fourcade C. CD3+ CD8+ CD56- clonal large granular lymphocyte leukaemia and HIV infection. Br J Haematol. 1997;98:444–5.

Perzova R, Graziano E, Sanghi S, et al. Increased seroreactivity to HERV-K10 peptides in patients with HTLV myelopathy. Virol J. 2013;10:360.

• Li W, Yang L, Harris RS, Lin L, Olson TL, Hamele CE, et al. Retrovirus insertion site analysis of LGL leukemia patient genomes. BMC Med Genet. 2019;12:88 This recent paper has shown that there are no new retrovirus insertions in LGL leukemia .

Chang H, Kamel-Reid S, Hussain N, Lipton J, Messner HA. T-cell large granular lymphocytic leukemia of donor origin occurring after allogeneic bone marrow transplantation for B-cell lymphoproliferative disorders. Am J Clin Pathol. 2005;123:196–9.

Gill H, Ip AHW, Leung R, So JCC, Pang AWK, Tse E, et al. Indolent T-cell large granular lymphocyte leukaemia after haematopoietic SCT: a clinicopathologic and molecular analysis. Bone Marrow Transplant. 2012;47:952–6.

Gentile TC, Hadlock KG, Uner AH, Delal B, Squiers E, Crowley S, et al. Large granular lymphocyte leukaemia occurring after renal transplantation. Br J Haematol. 1998;101:507–12.

• Alfano G, Fontana F, Colaci E, Mori G, Cerami C, Messerotti A, et al. T-cell large granular lymphocyte leukemia in solid organ transplant recipients: case series and review of the literature. Int J Hematol. 2019;110:313–21 This recent paper has identified T-LGL leukemia in patients who received solid organ transplantation .

Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest. 2001;107:351–62.

Clemente MJ, Wlodarski MW, Makishima H, Viny AD, Bretschneider I, Shaik M, et al. Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia. Blood. 2011;118:4384–93.

Kerr CM, Clemente MJ, Chomczynski PW, Przychodzen B, Nagata Y, Adema V, et al. Subclonal STAT3 mutations solidify clonal dominance. Blood Adv. 2019;3:917–21.

Shvidel L, Duksin C, Tzimanis A, Shtalrid M, Klepfish A, Sigler E, et al. Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders. Hematol J. 2002;3:32–7.

Kothapalli R, Nyland SB, Kusmartseva I, Bailey RD, McKeown TM, Loughran TP. Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. Int J Oncol. 2005;26:529–35.

Teramo A, Gattazzo C, Passeri F, et al. Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia. Blood. 2013;121(3843–54):S1.

Google Scholar  

Yang J, Liu X, Nyland SB, Zhang R, Ryland LK, Broeg K, et al. Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. Blood. 2010;115:51–60.

Zambello R, Facco M, Trentin L, et al. Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. Blood. 1997;89:201–11.

Chen J, Petrus M, Bamford R, Shih JH, Morris JC, Janik JE, et al. Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia. Blood. 2012;119:137–43.

Hodge DL, Yang J, Buschman MD, Schaughency PM, Dang H, Bere W, et al. Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias. Cancer Res. 2009;69:3986–94.

• Wang TT, Yang J, Zhang Y, Zhang M, Dubois S, Conlon KC, et al. IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability. Leukemia. 2019;33:1243–55 This paper describes ex vivo efficacy of BNZ-1 on LGL leukemia cells .

• Brammer JE, Sokol L, Tagaya Y, et al. Blockade of IL-15 utilizing Bnz-1, a selective γ-chain inhibiting peptide, is safe and has clinical activity in patients with T-cell large granular lymphocytic leukemia (T-LGLL): results of a phase I/II multi-center clinical trial. Blood. 2019;134:2835–5 This abstract describes the preliminary results of a phase I/II BNZ-1 clinical trial .

Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell. 2012;22:645–55.

Raess PW, Cascio MJ, Fan G, Press R, Druker BJ, Brewer D, et al. Concurrent STAT3, DNMT3A, and TET2 mutations in T-LGL leukemia with molecularly distinct clonal hematopoiesis of indeterminate potential. Am J Hematol. 2017;92:E6–8.

LeBlanc FR, Liu X, Hengst J, Fox T, Calvert V, Petricoin EF, et al. Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. Cancer Biol Ther. 2015;16:1830–40.

Kaelin WG. Common pitfalls in preclinical cancer target validation. Nat Rev Cancer. 2017;17:425–40.

Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20:273–86.

Lin A, Giuliano CJ, Palladino A, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aaw8412 .

Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate is a JAK/STAT pathway inhibitor. PLoS One. 2015;10:e0130078.

Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, et al. Methotrexate an old drug with new tricks. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20205023 .

Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238:787–93.

Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30:1663–9.

Article   PubMed   PubMed Central   Google Scholar  

Gamis AS, Alonzo TA, Perentesis JP, Meshinchi S, COG Acute Myeloid Leukemia Committee. Children’s Oncology Group’s 2013 blueprint for research: acute myeloid leukemia. Pediatr Blood Cancer. 2013;60:964–71.

Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M, et al. Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:957–63.

Vitanza NA. 50 years ago in TheJournal ofPediatrics: induction of remission in acute leukemia of childhood by combination of prednisone and either 6-mercaptopurine or methotrexate. J Pediatr. 2016;173:100.

O’Connor OA, Marchi E, Volinn W, Shi J, Mehrling T, Kim WS (2018) Strategy for assessing new drug value in orphan diseases: an international case match control analysis of the PROPEL study. JNCI Cancer Spectr 2:pky038.

Moosic KB, Paila U, Olson KC, Dziewulska K, Wang TT, Xing JC, et al. Genomics of LGL leukemia and select other rare leukemia/lymphomas. Best Pract Res Clin Haematol. 2019;32:196–206.

Andersson EI, Rajala HLM, Eldfors S, et al. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation. Blood Cancer J. 2013;3:e168.

Download references

Acknowledgments

We thank Bryna Shemo and Rachel Stidham for LGL Leukemia Registry support. We wish to extend a special thanks to the LGL Leukemia Registry patients for their enthusiastic support and interest in our research.

LGL leukemia research in the Loughran lab is supported by the National Cancer Institute of the National Institutes of Health under award number R01CA178393 and P30CA044579 (to TPL) and the NIH Cancer Research Training in Molecular Biology Award T32CA009109 (to KBM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Bess Family Charitable Fund, the LGL Leukemia Foundation, and a generous anonymous donor.

Author information

Karolina H. Dziewulska and Katharine B. Moosic contributed equally to this work.

Authors and Affiliations

Department of Medicine, Division of Hematology & Oncology, University of Virginia Cancer Center, PO Box 800334, Charlottesville, VA, 22908-0334, USA

HeeJin Cheon, Karolina H. Dziewulska, Katharine B. Moosic, Kristine C. Olson, David J. Feith & Thomas P. Loughran Jr.

Department of Biochemistry and Molecular Genetics, Charlottesville, VA, 22908, USA

HeeJin Cheon

Medical Scientist Training Program, Charlottesville, VA, 22908, USA

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

Karolina H. Dziewulska, Katharine B. Moosic & Alejandro A. Gru

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Thomas P. Loughran Jr. .

Ethics declarations

Conflict of interest.

Thomas P. Loughran, Jr. is on the Scientific Advisory Board and has stock options for Keystone Nano and Bioniz Therapeutics. Thomas P. Loughran and David J. Feith have received honoraria from Kymera Therapeutics. There are no conflicts of interest with the work presented in this manuscript.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on T Cell and Other Lymphoproliferative Malignancies

Rights and permissions

Reprints and permissions

About this article

Cheon, H., Dziewulska, K.H., Moosic, K.B. et al. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep 15 , 103–112 (2020). https://doi.org/10.1007/s11899-020-00565-6

Download citation

Published : 15 February 2020

Issue Date : April 2020

DOI : https://doi.org/10.1007/s11899-020-00565-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Large granular lymphocyte leukemia
• Autoimmunity
• Organ transplant
• Find a journal
• Publish with us
• Track your research

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

April 8, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Targeting vulnerability in B-cell development leads to novel drug combination for leukemia

by St. Jude Children's Research Hospital

Despite having an overall survival rate of 94%, B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, can prove challenging to treat, with survival among relapsed or resistant cases falling between 30-50%.

In recent work by St. Jude Children's Research Hospital, scientists discovered which tumor cells resist treatment and why. This enabled the rational design of a combination therapy that better controlled high-risk subtypes of B-ALL in mouse models. The findings were published today in Cancer Cell .

"We found a new explanation of B-ALL sensitivity to asparaginase, which is one of the most commonly used drugs for this disease," said senior co-corresponding author Jun J. Yang, Ph.D., St. Jude Department of Pharmacy and Pharmaceutical Sciences vice-chair. "Although asparaginase has been around for almost 50 years, the way we use this drug for ALL remains imprecise. This is partly because we still do not fully understand the mechanism by which it kills leukemia cells."

Scientists showed combining the classic drug asparaginase (chemotherapy) with a newer drug, venetoclax (a BCL-2 targeted therapy), was most effective at treating B-ALL in laboratory models. The combination reduced the number of leukemia cells more than either drug alone and worked faster. The improved effects were consistent across three different high-risk subtypes of this cancer.

"This discovery was enabled by single-cell systems biology analysis of B cell development and integration with B-ALL drug sensitivity profiling and bulk RNA-sequencing data," said co-corresponding author Jiyang Yu, Ph.D., St. Jude Department of Computational Biology interim chair. "Our single-cell network analysis revealed the protein BCL-2 as a hidden vulnerability in the asparaginase-resistant tumor developmental stage ."

"Administering asparaginase alongside venetoclax may lower the risk of ALL relapse, the major reason for treatment failure," said co-author Ching-Hon Pui, MD, St. Jude Department of Oncology Fahad Nassar Al-Rashid Endowed Chair of Leukemia Research. "Ideally, we aim for venetoclax to potentiate the anti-leukemia properties of asparaginase while keeping its toxicity levels in check. These concepts warrant further investigation in future clinical trials."

Venetoclax is already Food and Drug Administration–approved for use in other pediatric cancers, making it an attractive candidate. The drug has proven safe in those settings, paving the way for future approval in B-ALL treatment. The largest hurdle was understanding how venetoclax works with asparaginase to stop B-cell leukemia.

B-cell development stage is a challenge and vulnerability in B-ALL

B-ALL is a cancer derived from white blood cells called B cells. Under normal circumstances, B cells develop from immature to fully mature, passing through eight steps. In cancers, cells can get stuck in an intermediate stage of development. In a related disease, T-cell acute lymphoblastic leukemia ,

Yang and Yu previously found, as reported in Nature Cancer 2021, that the developmental stage where T cells get stuck determines their sensitivity to therapeutics. The researchers wanted to understand what made cells in a specific stage respond to which drug, hoping that such understanding would present new therapeutic opportunities.

"In this case, we found tumor B cells are stuck in two major stages," Yu said. "One is an earlier stage that is more resistant to asparaginase and another later stage that is more sensitive to it."

Yu looked at gene expression data from hundreds of thousands of individual cancerous B cells to understand what was different about them. After identifying the two dominant B-cell development stages of B-ALL, pre-pro-B (early) and pro-B (late), his lab looked for the genes upregulated in the resistant early cells to identify potential vulnerabilities to target therapeutically.

"The protein BCL-2 caught our attention, as it seems to be a driver of asparaginase-resistance in leukemia cells with pre-pro-B features," Yu said.

B cell lymphoma protein 2 (BCL-2) is a protein involved in cell death. Cancer cells use it to evade the systems that normally cause them to self-destruct. The protein is also downstream of mTOR, the protein targeted by asparaginase. Findings showed that BCL-2 was activated in cancer cells resistant to that drug. That resistance relationship motivated the scientists to try venetoclax, which targets the protein BCL-2, in a combination approach.

"When you add asparaginase, you hit mTOR signaling," Yang said. "In turn, that upregulates the BCL-2 activity, making the cells more sensitive to venetoclax."

The work also has implications for other cancers because incorrect development underlies many forms of the disease. Single-cell gene sequencing and analysis may provide similar opportunities to improve therapies in those contexts.

"We showed that developmental arrest of cancer cells can make them sensitive to certain drugs," Yang said. "Once we determine the pathways involved, we can find new drug combinations to improve treatment outcomes."

Explore further

Feedback to editors

New study highlights the benefit of touch on mental and physical health

17 minutes ago

Study finds treating heart attack patients with beta-blockers may be unnecessary

21 minutes ago

New technique sheds light on memory and learning

26 minutes ago

Saruparib demonstrates early efficacy in breast cancers with DNA repair defects in Phase I/II trial

34 minutes ago

Investigational therapeutic shows promise in preclinical pancreatic cancer model

Rogue immune cell that can cause poor antibody responses in chronic viral infections discovered

Youths with mood disorders 30% less likely to acquire driver's license than peers, researchers find

Study of twins provides new insights into immune defense in the womb

In the genetics of congenital heart disease, noncoding DNA fills in some blanks

Experimental drug could further reduce triglycerides in the blood in high-risk patients, trial shows

Related stories.

ABT199/Venetoclax synergism with thiotepa in acute myeloid leukemia (AML) cells

Mar 25, 2024

New research identifies promising drug combination for multiple myeloma treatment

New promising targeted drug for a rare leukemia

Feb 23, 2023

Technique for tracking resistant cancer cells could lead to new treatments for relapsing breast cancer patients

Dec 20, 2022

Research better characterizes a rare form of leukemia on the molecular level

Jan 9, 2024

Team finds cancer drug resistance genes and possibly how to limit their effects

Mar 9, 2020

Recommended for you

Clinical trial data show investigational cancer vaccine may elicit lasting immune response in pancreatic cancer

2 hours ago

Screening with a PSA test has a small impact on prostate cancer deaths but leads to overdiagnosis, finds study

Apr 6, 2024

Let us know if there is a problem with our content

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

AI Index Report

The AI Index Report tracks, collates, distills, and visualizes data related to artificial intelligence. Our mission is to provide unbiased, rigorously vetted, broadly sourced data in order for policymakers, researchers, executives, journalists, and the general public to develop a more thorough and nuanced understanding of the complex field of AI. The report aims to be the world’s most credible and authoritative source for data and insights about AI.

Read the 2023 AI Index Report

Coming Soon: 2024 AI Index Report!

The 2024 AI Index Report will be out April 15! Sign up for our mailing list to receive it in your inbox.

Steering Committee Co-Directors

Ray Perrault

Steering committee members.

Erik Brynjolfsson

John Etchemendy

Katrina Ligett

Terah Lyons

James Manyika

Juan Carlos Niebles

Vanessa Parli

Yoav Shoham

Russell Wald

Staff members.

Loredana Fattorini

Nestor Maslej

Letter from the co-directors.

AI has moved into its era of deployment; throughout 2022 and the beginning of 2023, new large-scale AI models have been released every month. These models, such as ChatGPT, Stable Diffusion, Whisper, and DALL-E 2, are capable of an increasingly broad range of tasks, from text manipulation and analysis, to image generation, to unprecedentedly good speech recognition. These systems demonstrate capabilities in question answering, and the generation of text, image, and code unimagined a decade ago, and they outperform the state of the art on many benchmarks, old and new. However, they are prone to hallucination, routinely biased, and can be tricked into serving nefarious aims, highlighting the complicated ethical challenges associated with their deployment.

Although 2022 was the first year in a decade where private AI investment decreased, AI is still a topic of great interest to policymakers, industry leaders, researchers, and the public. Policymakers are talking about AI more than ever before. Industry leaders that have integrated AI into their businesses are seeing tangible cost and revenue benefits. The number of AI publications and collaborations continues to increase. And the public is forming sharper opinions about AI and which elements they like or dislike.

AI will continue to improve and, as such, become a greater part of all our lives. Given the increased presence of this technology and its potential for massive disruption, we should all begin thinking more critically about how exactly we want AI to be developed and deployed. We should also ask questions about who is deploying it—as our analysis shows, AI is increasingly defined by the actions of a small set of private sector actors, rather than a broader range of societal actors. This year’s AI Index paints a picture of where we are so far with AI, in order to highlight what might await us in the future.

- Jack Clark and Ray Perrault

Our Supporting Partners

Analytics & Research Partners

Stay up to date on the AI Index by subscribing to the  Stanford HAI newsletter.

Help | Advanced Search

Computer Science > Computation and Language

Title: realm: reference resolution as language modeling.

Abstract: Reference resolution is an important problem, one that is essential to understand and successfully handle context of different kinds. This context includes both previous turns and context that pertains to non-conversational entities, such as entities on the user's screen or those running in the background. While LLMs have been shown to be extremely powerful for a variety of tasks, their use in reference resolution, particularly for non-conversational entities, remains underutilized. This paper demonstrates how LLMs can be used to create an extremely effective system to resolve references of various types, by showing how reference resolution can be converted into a language modeling problem, despite involving forms of entities like those on screen that are not traditionally conducive to being reduced to a text-only modality. We demonstrate large improvements over an existing system with similar functionality across different types of references, with our smallest model obtaining absolute gains of over 5% for on-screen references. We also benchmark against GPT-3.5 and GPT-4, with our smallest model achieving performance comparable to that of GPT-4, and our larger models substantially outperforming it.

Submission history

Access paper:.

• HTML (experimental)
• Other Formats

References & Citations

• Google Scholar
• Semantic Scholar

BibTeX formatted citation

Bibliographic and Citation Tools

Code, data and media associated with this article, recommenders and search tools.

• Institution

arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? Learn more about arXivLabs .

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts

Journal Information

Aims and Scope Leukemia  publishes high quality, peer reviewed research that covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance. Topics of interest include oncogenes, growth factors, stem cells, leukemia genomics, cell cycle, signal transduction, molecular targets for therapy and more. We publish a range of content types including original research articles, reviews, letters, correspondence and comments that elaborate on significant advances in the field and cover topical issues.

Why Publish in Leukemia ?

• Ranked in the top quartile of journals worldwide in the fields of oncology and hematology , we publish high quality, peer reviewed original content across all aspects of the research and treatment of leukemia and allied diseases.  
• We provide wide exposure and high visibility for your publication through our nature.com platform. We also offer funder-compliant open access options .
• Leading voices in the field across the globe form our expert editorial team , providing attractive turnaround times from first decision to publication. 

Journal Metrics

Article metrics such as number of downloads, citations and online attention are available from each article page, and provide an overview of the attention received by a paper.

2022 Citation Metrics

2-year Impact Factor*: 11.4 5-year Impact Factor*: 10.4 Immediacy index*: 2.8 Eigenfactor® score*: 0.04262 Article influence score*: 3.5 Journal Citation Indicator*: 1.95 SNIP**: 2.198 SJR***: 3.376

*2022 Journal Citation Reports® Science Edition (Clarivate Analytics, 2023) **Source-normalized Impact per Paper (Scopus) ***SCImago Journal Rank (Scopus)

2023 Peer Review Metrics

Submission to first editorial decision: 4 days Submission to Accept: 106 days

2023 Usage Metrics

Downloads: 2,535,447 Altmetric mentions: 4,878

Frequency 12 issues per year

Abstracted/indexed in: EBSCO Discovery Service Google Scholar OCLC Summon by ProQuest BIOSIS Current Contents/Life Sciences Science Citation Index Science Citation Index Expanded (SciSearch) SCOPUS EBSCO Academic Search EBSCO Advanced Placement Source EBSCO Biomedical Reference Collection EBSCO CINAHL EBSCO STM Source EBSCO TOC Premier INIS Atomindex

ISSN and eISSN International standard serial number (ISSN): 0887-6924 Electronic international standard serial number (eISSN): 1476-5551.

Newsfeeds Leukemia  now provides its latest table of contents as an RSS web feed. This allows users with an RSS reader to receive automatic updates whenever new content is added to these pages.

Receive  Leukemia 's current issue table of contents .

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Pacylex Pharmaceuticals Reports Zelenirstat Disrupts Oxidative Phosphorylation in Cancer Cells at AACR 2024

• Zelenirstat is a dual-action drug targeting pro-survival signaling and OXPHOS through deregulation of mitochondrial complex I.
• Stable disease was observed in eight (28%) patients in the Phase 1 study, mostly at the 210mg dose.
• Progression free and overall survival were significantly better in patients receiving 210mg compared to those receiving lower doses.

Edmonton, Alberta, Canada April 8, 2024. Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company focused on the development of a new class of targeted therapies, N-myristoyltransferase inhibitors (NMTi) for the treatment of hematologic and solid tumor cancers. Today Pacylex announced that new data demonstrating that zelenirstat, a proprietary, potent, NMTi, reduces Complex I formation and oxidative phosphorylation in the mitochondria of cancer cells , will be presented at the American Association for Cancer Research (AACR) Annual Meeting from April 5-10, 2024, in San Diego, California . This new insight may help account for the effect zelenirstat had on refractory/ relapsed (r/r) cancers in a recent Phase 1 study whose results are also presented.

A poster will be presented describing the Company’s Phase 1 study safety results and efficacy signals, as well as evidence for profound disruption of Complex I formation in mitochondria of cancer cell with concomitant loss of oxidative phosphorylation. The Company’s CEO, Dr. Michael Weickert , will be available during the poster session and for one-on-one meetings. The details of the poster are below:

“The evidence that zelenirstat disrupts energy production in the mitochondria of cancer cells has profound implications for cancer treatment since mitochondrial oxidative phosphorylation is required for metastasis and cancer stem cell survival. These two processes represent the major causes of death from cancer and cancer relapses respectively.”, said Dr. Luc Berthiaume, CSO of Pacylex. “Coupled with our previous evidence that zelenirstat strongly disrupts cancer cell signaling, we have now established two myristoylation-related mechanisms to explain selective sensitivity of cancer cells to NMT inhibition.” 

• For additional information, please visit www.pacylex.com .
• For more information:
• Pacylex Pharmaceuticals Contact: Michael J. Weickert
• CEO, Pacylex Pharmaceuticals, Inc.
• E: [email protected]
• P: 650-218-1840
• Twitter @Pacylex ( https://twitter.com/pacylex ) 
• LinkedIn ( www.linkedin.com/company/pacylex-pharma )
• Facebook ( https://www.facebook.com/pacylex )

#cancer, #lymphoma, #leukemia, #albertacancer, #Pacylex, #zelenirstat, #PCLX001, #UAlberta; #UAlberta_FoMD; #Worldslongestgame, #NHL, #zelenirstat #MedInvestOncology #OncologyInvesting

About zelenirstat (PCLX-001) Zelenirstat (formerly identified as PCLX-001) is a first-in-class, oral, small molecule NMTi being developed to treat patients with leukemia, lymphoma, and solid tumors. In animal models, zelenirstat selectively killed cancer cells in vitro and has been shown to regress hematologic malignancies and inhibit the growth of lung and breast cancer tumors. In AML models, zelenirstat killed leukemic stem enriched cell populations and allowed the regeneration and growth of normal bone marrow cells. About zelenirstat Phase 1 and 2 studies Pacylex completed the dose escalation phase of a Phase 1 multiple ascending dose safety, tolerability, and pharmacokinetics study on zelenirstat in r/r lymphoma and solid tumor patients (NCT04836195). A recommended Phase 2 dose was determined. Zelenirstat demonstrated an acceptable safety and tolerability profile, pharmacokinetics consistent with once daily oral dosing, and early signs of efficacy. Zelenirstat is currently being studied in a Phase 2a open-label study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of zelenirstat in patients with r/r B-cell non-Hodgkin Lymphoma (NHL) and a separate Phase 2a cohort in advanced r/r colorectal cancer who have progressed on all available standard therapies.  About Pacylex Pharmaceuticals Pacylex is a clinical-stage pharmaceutical company headquartered in Edmonton, Alberta, Canada, targeting hematologic and solid cancers with orally bioavailable NMT inhibitors. Zelenirstat is the lead drug in a new class of NMT inhibitors, enabling Pacylex to exploit NMTs as new clinical targets for cancer treatment. Pacylex is conducting a multi-center Phase 1/2a study in Canada in patients with R/R NHL and advanced solid tumors. The IND for a Phase 1 multiple ascending dose study in acute myeloid leukemia (AML) has been cleared and the FDA has granted zelenirstat both Orphan Drug Designation and Fast Track Designation for AML. The US Department of Defense is supporting the initial clinical investigation of zelenirstat in patients with AML. The Cure Cancer Foundation supported initial clinical studies through its World’s Longest Games.  Forward-Looking Statements This press release contains forward-looking statements and forward-looking information within the meaning of applicable securities laws, such as statements relating to future events or the Company’s future financial and operating performance, as well as the Company’s business plans, growth initiatives, and objectives and prospects. Generally, forward-looking statements and forward-looking information may be identified by the use of forward-looking terminology, including the words “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “should,” “plan,” “goal,” “expect,” “strategy,” “future,” “likely,” "proposed,” “scheduled,” “forecast,” “budget,” “could,” “would,” variations of such words of phrases and other similar expressions, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. However, the absence of these words does not mean that a statement is not forward looking. Forward-looking statements and forward-looking information are subject to numerous factors, risks and uncertainties that could cause actual results to differ materially, including, but not limited to, the Company’s ability to successfully execute on its business plans and strategies, avoid delays in planned clinical trials, hire and retain key personnel, obtain appropriate or necessary governmental approvals to market potential products and obtain future funding for product development and working capital on commercially reasonable terms, changes in laws, and  general macroeconomic conditions, including economic slowdowns, recessionary risks, rising inflation and interest rates, and supply chain disruptions. Forward-looking statements and forward-looking information are based on the beliefs of management as well as assumptions made by and information currently available to management as of the date hereof, and none of the Company or its affiliates undertakes any obligation to update or issue revisions to any forward-looking statements or forward-looking information contained herein to reflect any future events or circumstances, except as required by law. The foregoing does not constitute an offer or solicitation to acquire any securities in the Company or any related or associated entity or affiliate. The information contained herein is not intended as legal, tax, financial or investment advice. Furthermore, the information contained herein may not be applicable to or suitable for an individual’s specific circumstances or needs.

Get in Touch

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Leuk Res Rep

Acute myeloid leukemia with variant t(8;10;21)

Barbora bacova.

a Department of Haematology, 3rd Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady. Srobarova 50, 100 34, Prague 10, Czech Republic

Jiri Sobotka

b Laboratory of Medical Genetics, SPADIA LAB a.s., Ostrava, Czech Republic

Petra Kacirkova

c Central laboratories of the Faculty Hospital Kralovske Vinohrady, Czech Republic

Veronika Rivnacova

Ivana karlova/zubata.

d Department of Immunology, 3rd Faculty of Medicine, Charles University. Ruska 87, 100 00, Prague 10, Czech Republic

The t(8;21)(q22;q22) is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). Approximately 3–4% of AML cases are associated with additional chromosomal abnormalities. Their impact on the prognosis of the disease remains to be established. Here we report a case of t(8;10;21) AML with mutated c-KIT that shared key morphological features with classical t(8;21) leukemias, including the M2 morphology pattern and CD34, HLA-DR phenotype. The 63-year-old female was treated with two inductioncontaining Daunoribicine and Cytarabine and four cycles of intermediate-dose Cytarabine (1.5 g/m 2 ) and achieved long-lasting remission.

1. Introduction

The translocation t(8;21)(q22;q22) is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). This subtype is strongly associated with French-American-British (FAB) subtype M2 (WHO). Clinically, the disease is associated with a high remission rate with standard chemotherapy and prolonged survival when high-dose Cytarabine is administered [1] , [2] , [3] . Approximately 3–4% of t(8;21)(q22;q22) AML cases are associated with additional chromosomal abnormalities [4] . Their impact on the characteristics and outcomes of the disease is not completely understood.

2. Case presentation

A 63-year-old female was admitted for fatigue lasting one month and progressive dyspnea. The laboratory work-up revealed 60 × 10 9 /L of white blood cells, hemoglobin level of 74 g/L and 15 × 10 9 /L of platelets. As the differential white blood cell count contained 51% of myeloblasts with Auer rods, the bone marrow cytology was performed the next day.

The bone marrow aspirate smears were hypercellular, with massive (66%) infiltration by myeloblasts. The myeloblasts varied in diameter between 12–16 μm, and had round nuclei with one to four nucleoli and fine nuclear chromatin. The cytoplasm was scanty, moderately basophilic, often containing azurophilic granules and sporadic Auer rod or pseudo-Chédiak-Higashi inclusion. The proportion of promyelocytes was also elevated (9%), often having atypically shaped nuclei and granulation defects. More mature granulocytes were also often dysplastic – hypogranularity, agranularity, and unusually small myelocytes as well as pelgeroid changes were present. Erythropoiesis and megakaryopoiesis were almost absent ( Fig. 1 ).

The bone marrow aspirate. The bone marrow aspirate smears were hypercellular, with massive (66%) infiltration by myeloblasts. The myeloblast varied in diameter between 12–16 μm, and had round nuclei with one to four nucleoli and fine nuclear chromatin. The cytoplasm was scanty, moderately basophilic, often containing azurophilic granules and sporadic Auer rod or pseudo-Chédiak-Higashi inclusion. The proportion of promyelocytes was also elevated (9%), often having atypically shaped nuclei and granulation defects. More mature granulocytes were also often dysplastic – hypogranularity, agranularity, and unusually small myelocytes as well as pelgeroid changes were present. Erythropoiesis and megakaryopoiesis almost were absent.

The marrow blasts (42% of marrow cells) expressed CD34, CD17, HLA-DR…, CD33, CD56, CD38, MPO and aberrantly CD19. In addition to the blasts, the marrow contained 36% of immature cells of myeloid origin.

Routine cytogenetic analysis revealed complex chromosomal changes involving three chromosomes: 8, 10, and 21. The observation of breakpoints at 8q22 and 21q22 suggested rearrangements of the RUNX1 and RUNX1T1 genes. FISH analysis using a dual-color, dual-fusion RUNX1-RUNX1T1 probe revealed a specific RUNX1-RUNX1T1 fusion signal on the derivative chromosome. M-FISH analysis using a multi-color 24XCyte probe confirmed the results of routine chromosome analysis and revealed that part of the chromosome 8 material was translocated to chromosome 10, part of chromosome 10 moved to chromosome 21, and part of chromosome 21 was attached to chromosome 8 ( Fig. 2 A and ​ and2B). 2 B). The results of classical cytogenetic, FISH and M-FISH analysis revealed karyotype 46,XX,t(8;10;21)(q22;p14;q22) showing the variant of the t(8;21) translocation involving chromosome 10 as a third chromosome. No other secondary chromosomal changes were found.

A. Routine cytogenetic analysis. Routine cytogenetic analysis revealed complex chromosomal changes involving three chromosomes: 8, 10, and 21. B. FISH analysis. Using a dual-color, dual-fusion RUNX1-RUNX1T1 probe revealed a specific RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8.

The direct PCR sequencing revealed the RUNX1-RUNX1T1 fusion transcript and the direct PCR sequencing of exons 8, 9 and 17 of c-kit gene revealed the mutation NM_001093772.1:c.1250_1256delCTTACGAinsGGGC. Mutations of FLT3-ITD and NPM1 and presence of PML-RARA fusion transcript were ruled out by further examination.

Following three days of cytoreduction with 3 g hydroxyurea per day, the induction consisting of 7 days of Cytarabine 100 mg/m 2 and 3 days of Daunorubicin 90 mg/m 2 was started. The bone marrow cytology performed on day 14 of the induction revealed the persistence of leukemic cells (10% of myeloblasts by cytology and 12% by flow cytometry) in hypocellular bone marrow aspirate. According to institutional guidelines, a second induction consisting of 7 days of Cytarabine 100 mg/m 2 and 3 days of Daunorubicin 45 mg/m 2 was started on day 21 of the first induction. The treatment was well tolerated. The bone marrow cytology performed on day 25 of the second induction revealed aplastic bone marrow aspirate without trilinear haematopoiesis. Consistent with these findings, the peripheral blood smear contained 0.1 × 10 9 /L of white blood cells, a hemoglobin level of 90 g/L, and 10 × 10 9 /L of platelets. With G-CSF (Granulocyte Colony Stimulating Factor) support, the neutrophile recovery was achieved on day 39 of the second induction. The bone marrow cytology performed on day 45 of the second induction revealed incipient remission. The hypocellular bone marrow aspirate with normocellular fragments contained 1.8% of myeloblasts and trilinear hematopoiesis. The amount of RUNX1-RUNX1T1 transcripts decreased by 2 logs after the second induction. The treatment then consisted of 4 cycles of intermediate-dose Cytarabine 1.5 g/m 2 twice daily on days 1, 3, and 5. Regular examinations of the bone marrow confirmed lasting cytological remission; the RUNX1-RUNX1T1 transcript decreased slowly but regularly and dropped to zero upon completion of the fourth consolidation. Further examinations of the bone marrow also confirmed the remission and the patient is disease-free more than 7 years after the diagnosis.

The recent case shared key morphological features with classical t(8;21) AML including the M2 morphology pattern and CD34, HLA-DR… phenotype. As in one of the previously described cases, the recent case contained an elevated proportion of promyelocytes in the bone marrow. Lee and colleagues described a case of t(8;10;21) leukemia in an 11-year-old female that morphologically mimicked chronic myeloid leukemia [5] .

In addition to cytogenetic changes, the recent case harboured c-KIT mutation. This is not surprising, as c-KIT mutations commonly occur in core binding factor AMLs. As much as 25% of t(8;21) and 30% of inv(16) harbor the c-KIT mutation [6] . Currently, the prognostic significance of c-KIT mutation is not completely understood. In some, but not all studies the presence of c-KIT mutation was shown to be associated with higher incidence of relapse. [7] However, the prognostic significance of the mutation itself is overcome by the powerful prognostic significance of the minimal residual disease monitoring. [8] Ultimately, the negative MRD status after the 3 rd consolidation and the wish of the patient guided our decision not to proceed to the allogenic hematopoietic stem cell transplantation.

However, the treatment options would actually be much more varied. Fludarabine, cytarabine and idarubicine can be effective regimen as well. [9] Specifically, one should mention Gemtuzumab ozogamicin (GO) that was approved by FDA in 2017 for the treatment of newly diagnosed CD33-positive AML. Gemtuzumab ozogamicin improves the outcome in patients with AML, the benefit being particularly clear in patients with favourable cytogenetics. The meta-analysis of five randomized trials showed that the addition of GO to induction therapy provides absolute survival benefit of 20,7% in core-binding factor (CBF) AML. [10]

Additional treatment option is represented by tyrosine kinase inhibitors like avapritinib or dasatinib. The addition of dasatinib into frontline therapy and its further administration as a maintenance therapy reduced the relapse rate in KIT-mutated CBF AML to levels comparable to KIT-wt CBF AML. [ 11 , 12 ]

3. Conclusion

t(8;21) is associated with a high remission rate with standard chemotherapy and prolonged survival when high-dose Cytarabine is administered [3] . The prognostic impact of additional molecular and cytogenetic changes is still a matter of debate. This uncertainty is linked mainly to the rarity of the variants. Whereas t(8;21) accounts for approximately 5–10% of AML [ 1 , 2 ], the additional cytogenetic changes are present in 3–4% [4] . As it is unrealistic to conduct a prospective study, the only way to evaluate their impact on the prognosis is to publish case reports or small patient series.

Authors’ contributions

Study conception and design: J.N. Acquisition, analysis and interpretation of data: B.B., J.N., J.S., P.K., V.R., I.K/Z. Drafting of manuscript: J.N. All authors read and approved the final manuscript.

Declaration of Competing Interest

The research has been performed in accordance with the Declaration of Helsinki. All data generated or analysed during this study are included in this published article.

The authors declare that they have no competing interests.

The work was supported by the research project Q28-PROGRES awarded by the 3 rd Faculty of Medicine, Charles University, Czech Republic. The funding body had no role in the design of the study, the collection, analysis, and interpretation of data, nor in the writing of the manuscript.

Acknowledgements

We would like to thank Nicholas J. McRae, PhD, for editing and correcting the English text.

Read our research on: Gun Policy | International Conflict | Election 2024

Regions & Countries

What’s it like to be a teacher in america today, public k-12 teachers are stressed about their jobs and few are optimistic about the future of education; many say poverty, absenteeism and mental health are major problems at their school.

Pew Research Center conducted this study to better understand the views and experiences of public K-12 school teachers. The analysis in this report is based on an online survey of 2,531 U.S. public K-12 teachers conducted from Oct. 17 to Nov. 14, 2023. The teachers surveyed are members of RAND’s American Teacher Panel, a nationally representative panel of public K-12 school teachers recruited through MDR Education. Survey data is weighted to state and national teacher characteristics to account for differences in sampling and response to ensure they are representative of the target population.

Here are the questions used for this report , along with responses, and the survey methodology .

Low-poverty , medium-poverty and high-poverty schools are based on the percentage of students eligible for free and reduced-price lunch, as reported by the National Center for Education Statistics (less than 40%, 40%-59% and 60% or more, respectively).

Secondary schools include both middle schools and high schools.

All references to party affiliation include those who lean toward that party. Republicans include those who identify as Republicans and those who say they lean toward the Republican Party. Democrats include those who identify as Democrats and those who say they lean toward the Democratic Party.

Public K-12 schools in the United States face a host of challenges these days – from teacher shortages to the lingering effects of COVID-19 learning loss to political battles over curriculum .

In the midst of all this, teachers express low levels of satisfaction with their jobs. In fact, they’re much less satisfied than U.S. workers overall.

Here’s how public K-12 teachers are feeling about their jobs:

• 77% say their job is frequently stressful.
• 68% say it’s overwhelming.
• 70% say their school is understaffed.
• 52% say they would not advise a young person starting out today to become a teacher.

When it comes to how their students are doing in school, teachers are relatively downbeat about both academic performance and behavior.

Here’s how public K-12 teachers rate academic performance and behavior at their school:

• 48% say the academic performance of most students at their school is fair or poor. A third say it’s good, and only 17% describe it as excellent or very good.
• 49% say the behavior of most students at their school is fair or poor; 35% say it’s good and 13% say it’s excellent or very good.

The COVID-19 pandemic likely compounded these issues. About eight-in-ten teachers (among those who have been teaching for at least a year) say the lasting impact of the pandemic on students’ behavior, academic performance and emotional well-being has been very or somewhat negative.

Assessments of student performance and behavior differ widely by school poverty level. 1 Teachers in high-poverty schools have a much more negative outlook. But feelings of stress and dissatisfaction among teachers are fairly universal, regardless of where they teach.

Related: What Public K-12 Teachers Want Americans To Know About Teaching

As they navigate these challenges, teachers don’t feel they’re getting the support or reinforcement they need from parents.

Majorities of teachers say parents are doing too little when it comes to holding their children accountable if they misbehave in school, helping them with their schoolwork and ensuring their attendance.

Teachers in high- and medium-poverty schools are more likely than those in low-poverty schools to say parents are doing too little in each of these areas.

These findings are based on a survey of 2,531 U.S. public K-12 teachers conducted Oct. 17-Nov. 14, 2023, using the RAND American Teacher Panel. 2 The survey looks at the following aspects of teachers’ experiences:

• Teachers’ job satisfaction (Chapter 1)
• How teachers manage their workload (Chapter 2)
• Problems students are facing at public K-12 schools (Chapter 3)
• Challenges in the classroom (Chapter 4)
• Teachers’ views of parent involvement (Chapter 5)
• Teachers’ views on the state of public K-12 education (Chapter 6)

Problems students are facing

We asked teachers about some of the challenges students at their school are facing. Three problems topped the list:

• Poverty (53% say this is a major problem among students who attend their school)
• Chronic absenteeism (49%)
• Anxiety and depression (48%)

Chronic absenteeism (that is, students missing a substantial number of school days) is a particular challenge at high schools, with 61% of high school teachers saying this is a major problem where they teach. By comparison, 46% of middle school teachers and 43% of elementary school teachers say the same.

Anxiety and depression are viewed as a more serious problem at the secondary school level: 69% of high school teachers and 57% of middle school teachers say this is a major problem among their students, compared with 29% of elementary school teachers.

Fewer teachers (20%) view bullying as a major problem at their school, though the share is significantly higher among middle school teachers (34%).

A look inside the classroom

We also asked teachers how things are going in their classroom and specifically about some of the issues that may get in the way of teaching.

• 47% of teachers say students showing little or no interest in learning is a major problem in their classroom. The share rises to 58% among high school teachers.
• 33% say students being distracted by their cellphones is a major problem. This is particularly an issue for high school teachers, with 72% saying this is a major problem.
• About one-in-five teachers say students getting up and walking around when they’re not supposed to and being disrespectful toward them (21% each) are major problems. Teachers in elementary and middle schools are more likely than those in high schools to see these as challenges.

A majority of teachers (68%) say they’ve experienced verbal abuse from a student – such as being yelled at or threatened. Some 21% say this happens at least a few times a month.

Physical violence is less common. Even so, 40% of teachers say a student has been violent toward them , with 9% saying this happens at least a few times a month.

About two-thirds of teachers (66%) say that the current discipline practices at their school are very or somewhat mild. Only 2% say the discipline practices at their school are very or somewhat harsh, while 31% say they are neither harsh nor mild. Most teachers (67%) say teachers themselves don’t have enough influence in determining discipline practices at their school.

Behavioral issues and mental health challenges

In addition to their teaching duties, a majority of teachers (58%) say they have to address behavioral issues in their classroom every day. About three-in-ten teachers (28%) say they have to help students with mental health challenges daily.

In each of these areas, elementary and middle school teachers are more likely than those at the high school level to say they do these things on a daily basis.

And teachers in high-poverty schools are more likely than those in medium- and low-poverty schools to say they deal with these issues each day.

Cellphone policies and enforcement

Most teachers (82%) say their school or district has policies regarding cellphone use in the classroom.

Of those, 56% say these policies are at least somewhat easy to enforce, 30% say they’re difficult to enforce, and 14% say they’re neither easy nor difficult to enforce.

Experiences with cellphone policies vary widely across school levels. High school teachers (60%) are much more likely than middle school (30%) and elementary school teachers (12%) to say the policies are difficult to enforce (among those who say their school or district has a cellphone policy).

How teachers are experiencing their jobs

Thinking about the various aspects of their jobs, teachers are most satisfied with their relationship with other teachers at their school (71% are extremely or very satisfied).

They’re least satisfied with how much they’re paid – only 15% are extremely or very satisfied with their pay, while 51% are not too or not at all satisfied.

Among teachers who don’t plan to retire or stop working this year, 29% say it’s at least somewhat likely they will look for a new job in the 2023-24 school year. Within that group, 40% say they would look for a job outside of education, 29% say they’d seek a non-teaching job in education, and only 18% say they’d look for a teaching job at another public K-12 school.

Do teachers find their work fulfilling and enjoyable?

Overall, 56% of teachers say they find their job to be fulfilling extremely often or often; 53% say their job is enjoyable. These are significantly lower than the shares who say their job is frequently stressful (77%) or overwhelming (68%).

Positive experiences are more common among newer teachers. Two-thirds of those who’ve been teaching less than six years say their work is fulfilling extremely often or often, and 62% of this group says their work is frequently enjoyable.

Teachers with longer tenures are somewhat less likely to feel this way. For example, 48% of those who’ve been teaching for six to 10 years say their work is frequently enjoyable.

Balancing the workload

Most teachers (84%) say there’s not enough time during their regular work hours to do tasks like grading, lesson planning, paperwork and answering work emails.

Among those who feel this way, 81% say simply having too much work is a major reason.

Many also point to having to spend time helping students outside the classroom, performing non-teaching duties like lunch duty, and covering other teachers’ classrooms as at least minor reasons they don’t have enough time to get all their work done.

A majority of teachers (54%) say it’s very or somewhat difficult for them to balance work and their personal life. About one-in-four (26%) say it’s very or somewhat easy for them to balance these things, and 20% say it’s neither easy nor difficult.

Among teachers, women are more likely than men to say work-life balance is difficult for them (57% vs. 43%). Women teachers are also more likely to say they often find their job stressful or overwhelming.

How teachers view the education system

A large majority of teachers (82%) say the overall state of public K-12 education has gotten worse in the past five years.

And very few are optimistic about the next five years: Only 20% of teachers say public K-12 education will be a lot or somewhat better five years from now. A narrow majority (53%) say it will be worse.

Among teachers who think things have gotten worse in recent years, majorities say the current political climate (60%) and the lasting effects of the COVID-19 pandemic (57%) are major reasons. A sizable share (46%) also point to changes in the availability of funding and resources.

Related:  About half of Americans say public K-12 education is going in the wrong direction

Which political party do teachers trust more to deal with educational challenges?

On balance, more teachers say they trust the Democratic Party than say they trust the Republican Party to do a better job handling key issues facing the K-12 education system. But three-in-ten or more across the following issues say they don’t trust either party:

• Shaping school curriculum (42% say they trust neither party)
• Ensuring teachers have adequate pay and benefits (35%)
• Making schools safer (35%)
• Ensuring adequate funding for schools (33%)
• Ensuring all students have equal access to high-quality K-12 education (31%)

A majority of public K-12 teachers (58%) identify or lean toward the Democratic Party. This is higher than the share among the general public (47%).

• Poverty levels are based on the percentage of students in the school who are eligible for free and reduced-price lunch. ↩
• For details, refer to the Methodology section of the report. ↩
• Urban, suburban and rural schools are based on the location of the school as reported by the National Center for Education Statistics (rural includes town). Definitions match those used by the U.S. Census Bureau. ↩

Social Trends Monthly Newsletter

Sign up to to receive a monthly digest of the Center's latest research on the attitudes and behaviors of Americans in key realms of daily life

Report Materials

Table of contents, ‘back to school’ means anytime from late july to after labor day, depending on where in the u.s. you live, among many u.s. children, reading for fun has become less common, federal data shows, most european students learn english in school, for u.s. teens today, summer means more schooling and less leisure time than in the past, about one-in-six u.s. teachers work second jobs – and not just in the summer, most popular.

About Pew Research Center Pew Research Center is a nonpartisan fact tank that informs the public about the issues, attitudes and trends shaping the world. It conducts public opinion polling, demographic research, media content analysis and other empirical social science research. Pew Research Center does not take policy positions. It is a subsidiary of The Pew Charitable Trusts .