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Genetic landscape of chronic myeloid leukemia

  • Progress in Hematology
  • Chronic myeloid leukemia: the cutting-edge evidence and things we should know
  • Published:
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Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the BCR::ABL1 fusion gene, which aberrantly activates ABL1 kinase and promotes the overproduction of leukemic cells. CML typically develops in the chronic phase (CP) and progresses to a blast crisis (BC) after years without effective treatment. Although prognosis has substantially improved after the development of tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 oncoprotein, some patients still experience TKI resistance and poor prognosis. One of the mechanisms of TKI resistance is ABL1 kinase domain mutations, which are found in approximately half of the cases, newly acquired during treatment. Moreover, genetic studies have revealed that CML patients carry additional mutations that are also observed in other myeloid neoplasms. ASXL1 mutations are often found in both CP and BC, whereas other mutations, such as those in RUNX1, IKZF1, and TP53, are preferentially found in BC. The presence of additional mutations, such as ASXL1 mutations, is a potential biomarker for predicting therapeutic efficacy. The mechanisms by which these additional mutations affect disease subtypes, drug resistance, and prognosis need to be elucidated. In this review, we have summarized and discussed the landscape and clinical impact of genetic abnormalities in CML.

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References

  1. Hehlmann R. How I treat CML blast crisis. Blood. 2012;120:737–47.

    Article  CAS  Google Scholar 

  2. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European leukemianet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    Article  CAS  Google Scholar 

  3. Radivoyevitch T, Weaver D, Hobbs B, Maciejewski JP, Hehlmann R, Jiang Q, et al. Do persons with chronic myeloid leukaemia have normal or near normal survival? Leukemia. 2020;34:333–5.

    Article  Google Scholar 

  4. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80.

    Article  CAS  Google Scholar 

  5. Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37:530–42.

    Article  CAS  Google Scholar 

  6. Soverini S, de Benedittis C, Mancini M, Martinelli G. Mutations in the BCR-ABL1 kinase domain and elsewhere in chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(Suppl):S120–8.

    Article  Google Scholar 

  7. Bavaro L, Martelli M, Cavo M, Soverini S. Mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update. Int J Mol Sci. 2019;20:6141.

    Article  CAS  Google Scholar 

  8. Mitani K, Nagata Y, Sasaki K, Yoshida K, Chiba K, Tanaka H, et al. Somatic mosaicism in chronic myeloid leukemia in remission. Blood. 2016;128:2863–6.

    Article  CAS  Google Scholar 

  9. Togasaki E, Takeda J, Yoshida K, Shiozawa Y, Takeuchi M, Oshima M, et al. Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia. Blood Cancer J. 2017;7: e559.

    Article  CAS  Google Scholar 

  10. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.

    Article  CAS  Google Scholar 

  11. Ogawa S. Genetics of MDS. Blood. 2019;133:1049–59.

    Article  CAS  Google Scholar 

  12. Ochi Y, Kon A, Sakata T, Nakagawa MM, Nakazawa N, Kakuta M, et al. Combined cohesin-RUNX1 deficiency synergistically perturbs chromatin looping and causes myelodysplastic syndromes. Cancer Discov. 2020;10:836–53.

    Article  CAS  Google Scholar 

  13. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. New Engl J Med. 2016;374:2209–21.

    Article  CAS  Google Scholar 

  14. Ochi Y, Ogawa S. Chromatin-spliceosome mutations in acute myeloid leukemia. Cancers. 2021;13:1232.

    Article  CAS  Google Scholar 

  15. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31.

    Article  CAS  Google Scholar 

  16. Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103:4010–22.

    Article  CAS  Google Scholar 

  17. Hosoya N, Sanada M, Nannya Y, Nakazaki K, Wang L, Hangaishi A, et al. Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. Genes Chromosomes Cancer. 2006;45:482–94.

    Article  CAS  Google Scholar 

  18. Nowak D, Ogawa S, Müschen M, Kato M, Kawamata N, Meixel A, et al. SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations. Blood. 2010;115:1049–53.

    Article  CAS  Google Scholar 

  19. Makishima H, Jankowska AM, McDevitt MA, O’Keefe C, Dujardin S, Cazzolli H, et al. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood. 2011;117:e198-206.

    Article  CAS  Google Scholar 

  20. Schmidt M, Rinke J, Schäfer V, Schnittger S, Kohlmann A, Obstfelder E, et al. Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Leukemia. 2014;28:2292–9.

    Article  CAS  Google Scholar 

  21. Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132:948–61.

    Article  CAS  Google Scholar 

  22. Magistroni V, Mauri M, D’Aliberti D, Mezzatesta C, Crespiatico I, Nava M, et al. De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways. Haematologica. 2019;104:1789–97.

    Article  CAS  Google Scholar 

  23. Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020;135:2337–53.

    Article  Google Scholar 

  24. Ochi Y, Yoshida K, Huang Y-J, Kuo M-C, Nannya Y, Sasaki K, et al. Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia. Nat Commun. 2021;12:2833.

    Article  CAS  Google Scholar 

  25. Kim T, Tyndel MS, Kim HJ, Ahn J-S, Choi SH, Park HJ, et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy. Blood. 2017;129:38–47.

    Article  CAS  Google Scholar 

  26. Mologni L, Piazza R, Khandelwal P, Pirola A, Gambacorti-Passerini C. Somatic mutations identified at diagnosis by exome sequencing can predict response to imatinib in chronic phase chronic myeloid leukemia (CML) patients. Am J Hematol. 2017;92:E623–5.

    Article  CAS  Google Scholar 

  27. Nteliopoulos G, Bazeos A, Claudiani S, Gerrard G, Curry E, Szydlo R, et al. Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors. Haematologica. 2019;104:2400–9.

    Article  CAS  Google Scholar 

  28. Bidikian A, Kantarjian H, Jabbour E, Short NJ, Patel K, Ravandi F, et al. Prognostic impact of ASXL1 mutations in chronic phase chronic myeloid leukemia. Blood Cancer J. 2022;12:144.

    Article  Google Scholar 

  29. Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: cohort study of 477 patients. Cancer. 2017;123:4391–402.

    Article  CAS  Google Scholar 

  30. Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127:2742–50.

    Article  CAS  Google Scholar 

  31. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345–77.

    Article  Google Scholar 

  32. Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019;33:1835–50.

    Article  Google Scholar 

  33. Corm S, Biggio V, Roche-Lestienne C, Laï J-L, Yakoub-Agha I, Philippe N, et al. Coexistence of AML1/RUNX1 and BCR-ABL point mutations in an imatinib-resistant form of CML. Leukemia. 2005;19:1991–2.

    Article  CAS  Google Scholar 

  34. Roche-Lestienne C, Deluche L, Corm S, Tigaud I, Joha S, Philippe N, et al. RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. Blood. 2008;111:3735–41.

    Article  CAS  Google Scholar 

  35. Roche-Lestienne C, Marceau A, Labis E, Nibourel O, Coiteux V, Guilhot J, et al. Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia. Leukemia. 2011;25:1661–4.

    Article  CAS  Google Scholar 

  36. Menezes J, Salgado RN, Acquadro F, Gómez-López G, Carralero MC, Barroso A, et al. ASXL1, TP53 and IKZF3 mutations are present in the chronic phase and blast crisis of chronic myeloid leukemia. Blood Cancer J. 2013;3: e157.

    Article  CAS  Google Scholar 

  37. Ernst T, Schmidt M, Rinke J, Schäfer V, Waldau A, Obstfelder E, et al. Molecularly defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Blood. 2014;124:4513–4513.

    Article  Google Scholar 

  38. Ernst T, Busch M, Rinke J, Ernst J, Haferlach C, Beck JF, et al. Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia. Leukemia. 2018;32:2046–9.

    Article  CAS  Google Scholar 

  39. Asada S, Fujino T, Goyama S, Kitamura T. The role of ASXL1 in hematopoiesis and myeloid malignancies. Cell Mol Life Sci. 2019;76:2511–23.

    Article  CAS  Google Scholar 

  40. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New Engl J Med. 2014;371:2488–98.

    Article  Google Scholar 

  41. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New Engl J Med. 2014;371:2477–87.

    Article  Google Scholar 

  42. Saiki R, Momozawa Y, Nannya Y, Nakagawa MM, Ochi Y, Yoshizato T, et al. Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis. Nat Med. 2021;27:1239–49.

    Article  CAS  Google Scholar 

  43. Adnan Awad S, Kankainen M, Ojala T, Koskenvesa P, Eldfors S, Ghimire B, et al. Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia. Blood Adv. 2020;4:546–59.

    Article  Google Scholar 

  44. Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017;129:2070–82.

    Article  CAS  Google Scholar 

  45. Bergink S, Jentsch S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature. 2009;458:461–7.

    Article  CAS  Google Scholar 

  46. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, et al. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J. 1994;13:504–10.

    Article  CAS  Google Scholar 

  47. Paquette RL, Nicoll J, Chalukya M, Elashoff D, Shah NP, Sawyers C, et al. Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors. Cancer Genet. 2011;204:392–7.

    Article  CAS  Google Scholar 

  48. Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D. T(3;21)(q26;Q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Cancer. 2006;106:1730–8.

    Article  CAS  Google Scholar 

  49. Wang W, Tang G, Cortes JE, Liu H, Ai D, Yin CC, et al. Chromosomal rearrangement involving 11q23 locus in chronic myelogenous leukemia: a rare phenomenon frequently associated with disease progression and poor prognosis. J Hematol Oncol. 2015;8:32.

    Article  Google Scholar 

  50. Stass S, Mirro J, Melvin S, Pui CH, Murphy SB, Williams D. Lineage switch in acute leukemia. Blood. 1984;64:701–6.

    Article  CAS  Google Scholar 

  51. Gagnon GA, Childs CC, LeMaistre A, Keating M, Cork A, Trujillo JM, et al. Molecular heterogeneity in acute leukemia lineage switch. Blood. 1989;74:2088–95.

    Article  CAS  Google Scholar 

  52. Feldman AL, Arber DA, Pittaluga S, Martinez A, Burke JS, Raffeld M, et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood. 2008;111:5433–9.

    Article  CAS  Google Scholar 

  53. Ochi Y, Hiramoto N, Yoshizato T, Ono Y, Takeda J, Shiozawa Y, et al. Clonally related diffuse large B-cell lymphoma and interdigitating dendritic cell sarcoma sharing MYC translocation. Haematologica. 2018;103:e553–6.

    Article  CAS  Google Scholar 

  54. Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26:1549–56.

    Article  CAS  Google Scholar 

  55. Takeda J, Yoshida K, Nakagawa MM, Nannya Y, Yoda A, Saiki R, et al. Amplified EPOR/JAK2 genes define a unique subtype of acute erythroid leukemia. Blood Cancer Discov. 2022;3:410–27.

    Article  Google Scholar 

  56. Mohanty S, Heuser M. Mouse models of frequently mutated genes in acute myeloid leukemia. Cancers (Basel). 2021;13:6192.

    Article  CAS  Google Scholar 

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  1. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, F-Building, Yoshida-Konoe-Cho, Sakyo-Ku, Kyoto, 606-8501, Japan

    Yotaro Ochi

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Ochi, Y. Genetic landscape of chronic myeloid leukemia. Int J Hematol 117, 30–36 (2023). https://doi.org/10.1007/s12185-022-03510-w

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  • DOI: https://doi.org/10.1007/s12185-022-03510-w

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