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Chronic myelogenous leukemia

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Leukemia volume 33, pages 1835–1850 (2019)Cite this article

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Abstract

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

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References

  1. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:1108–35.

    PubMed  Google Scholar 

  3. Ashley EA. Towards precision medicine. Nat Rev Genet. 2016;17:507–22.

    CAS  PubMed  Google Scholar 

  4. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    PubMed  PubMed Central  Google Scholar 

  5. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–99.

    CAS  PubMed  Google Scholar 

  6. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118:686–92.

    CAS  PubMed  Google Scholar 

  7. Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30:48–56.

    CAS  PubMed  Google Scholar 

  8. Than H, Lye WK, Sng C, Allen JC Jr., Ong ST, Chuah C. BIM deletion polymorphism profiling complements prognostic values of risk scores in imatinib-treated Asian chronic myeloid leukemia patients. Leuk Lymphoma. 2019;60:234–7.

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  10. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shlush LI. Age-related clonal hematopoiesis. Blood. 2018;131:496–504.

    CAS  PubMed  Google Scholar 

  12. Nazha A, Narkhede M, Radivoyevitch T, Seastone DJ, Patel BJ, Gerds AT, et al. Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Leukemia. 2016;30:2214–20.

    CAS  PubMed  Google Scholar 

  13. Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and Personalized Prognosis in Myeloproliferative Neoplasms. N Engl J Med. 2018;379:1416–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Corm S, Biggio V, Roche-Lestienne C, Lai JL, 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.

    CAS  PubMed  Google Scholar 

  15. Coyle T, Najfeld V. Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis. Am J Hematol. 1988;27:56–9.

    CAS  PubMed  Google Scholar 

  16. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood. 1999;93:1817–24.

    CAS  PubMed  Google Scholar 

  17. Roumier C, Fenaux P, Lafage M, Imbert M, Eclache V, Preudhomme C. New mechanisms of AML1 gene alteration in hematological malignancies. Leukemia. 2003;17:9–16.

    CAS  PubMed  Google Scholar 

  18. Ichikawa M, Asai T, Saito T, Yamamoto G, Seo S, Yamazaki I, et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med. 2004;10:299–304.

    CAS  PubMed  Google Scholar 

  19. Mangan JK, Speck NA. RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making. Crit Rev Oncog. 2011;16:77–91.

    PubMed  PubMed Central  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. Soverini S, Score J, Iacobucci I, Poerio A, Lonetti A, Gnani A, et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia. 2011;25:178–81.

    CAS  PubMed  Google Scholar 

  22. 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.

    CAS  PubMed  Google Scholar 

  23. Menezes J, Salgado RN, Acquadro F, Gomez-Lopez 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Watkins DB, Hughes TP, White DL, D’Andrea RJ. NPM1 mutations occur rarely or not at all in chronic myeloid leukaemia patients in chronic phase or blast crisis. Leukemia. 2013;27:489–90.

    CAS  PubMed  Google Scholar 

  25. Schmidt M, Rinke J, Schafer 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.

    CAS  PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. Valikhani A, Poopak B, Ferdowsi S, Azizi Tabesh G, Ghaffari SH, Saraf Kazeruoni E, et al. ASXL1 and JAK2V617F gene mutation screening in Iranian patients with chronic myeloid leukemia. Asia Pac J Clin Oncol. 2017;13:e41–7.

    PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sloma I, Mitjavila-Garcia MT, Feraud O, Griscelli F, Oudrhiri N, El Marsafy S, et al. Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia. Exp Hematol. 2017;53:48–58.

    CAS  PubMed  Google Scholar 

  31. Kim T, Tyndel MS, Kim HJ, Ahn JS, 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.

    CAS  PubMed  Google Scholar 

  32. Nteliopoulos G, Bazeos A, Claudiani C, Gerrard G, Curry C, 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. pii: haematol.2018.200220. https://doi.org/10.3324/haematol.2018.200220. [Epub ahead of print].

  33. Sondka Z, Bamford S, Cole CG, Ward SA, Dunham I, Forbes SA. The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Nat Rev Cancer. 2018;18:696–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fialkow P, Martin P, Najfeld V, Penfold G, Jacobson R, Hansen J. Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood. 1981;58:158–63.

    CAS  PubMed  Google Scholar 

  35. Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, Al Hinai A, Zeilemaker A, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:1189–99.

    CAS  PubMed  Google Scholar 

  36. 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.

    CAS  PubMed  Google Scholar 

  37. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107:76–94.

    CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ahuja H, Bar-Eli M, Arlin Z, Advani S, Allen SL, Goldman J, et al. The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. J Clin Invest. 1991;87:2042–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Feinstein E, Cimino G, Gale RP, Alimena G, Berthier R, Kishi K, et al. p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci USA. 1991;88:6293–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Nakai H, Misawa S, Toguchida J, Yandell DW, Ishizaki K. Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p. Cancer Res. 1992;52:6588–93.

    CAS  PubMed  Google Scholar 

  42. Zhang SJ, Ma LY, Huang QH, Li G, Gu BW, Gao XD, et al. Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci USA. 2008;105:2076–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.

    CAS  PubMed  Google Scholar 

  44. Piccaluga PP, Sabattini E, Bacci F, Agostinelli C, Righi S, Salmi F, et al. Cytoplasmic mutated nucleophosmin (NPM1) in blast crisis of chronic myeloid leukaemia. Leukemia. 2009;23:1370–1.

    CAS  PubMed  Google Scholar 

  45. Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R, et al. High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia. 2010;24:1139–45.

    CAS  PubMed  Google Scholar 

  46. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia. 2011;25:557–60.

    CAS  PubMed  Google Scholar 

  48. Konoplev S, Yin CC, Kornblau SM, Kantarjian HM, Konopleva M, Andreeff M, et al. Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma. 2013;54:138–44.

    CAS  PubMed  Google Scholar 

  49. Huang Y, Zheng J, Hu JD, Wu YA, Zheng XY, Liu TB, et al. Discovery of somatic mutations in the progression of chronic myeloid leukemia by whole-exome sequencing. Genet Mol Res. 2014;13:945–53.

    CAS  PubMed  Google Scholar 

  50. Kim T, Tyndel MS, Zhang Z, Ahn J, Choi S, Szardenings M, et al. Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy. Leuk Res. 2017;59:142–8.

    CAS  PubMed  Google Scholar 

  51. Sklarz LM, Wittke C, Krohn S, GROßE-Thie C, Junghanss C, Murua Escobar H, et al. Genetic mutations in a patient with chronic myeloid leukemia showing blast crisis 10 years after presentation. Anticancer Res. 2018;38:3961–6.

    PubMed  Google Scholar 

  52. Adnan Awad S, Kankainen M, Eldfors S, Yadav B, Kytölä S, Ellonen P, et al. Identification of progression-associated mutations in chronic myeloid leukemia (CML) by comparative genomic analysis (Abstract). Blood. 2017;130:250–50.

    Google Scholar 

  53. Ochi Y, Yoshida K, Huang Y-J, Kuo M-C, Shiozawa Y, Nannya Y, et al. Molecular profiling of blastic transformation in chronic myeloid leukemia (Abstract). Blood. 2018;132:1725–25.

    Google Scholar 

  54. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12:7374–9.

    CAS  PubMed  Google Scholar 

  55. Cortes J, Rousselot P, Kim D-W, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207–13.

    CAS  PubMed  Google Scholar 

  56. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114:5426–35.

    CAS  PubMed  Google Scholar 

  57. 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.

    CAS  PubMed  Google Scholar 

  58. Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2017;32:273.

    PubMed  PubMed Central  Google Scholar 

  59. Salem A, Loghavi S, Tang G, Huh YO, Jabbour EJ, Kantarjian H, et al. Myeloid neoplasms with concurrent BCR-ABL1 and CBFB rearrangements: a series of 10 cases of a clinically aggressive neoplasm. Am J Hematol. 2017;92:520–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jan M, Majeti R. Clonal evolution of acute leukemia genomes. Oncogene. 2013;32:135–40.

    CAS  PubMed  Google Scholar 

  61. 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. pii: haematol.2017.179937. https://doi.org/10.3324/haematol.2017.179937. [Epub ahead of print].

  62. Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Google Scholar 

  63. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23:2183–6.

    CAS  PubMed  Google Scholar 

  65. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2018;47:D886–94.

    PubMed Central  Google Scholar 

  67. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.

    CAS  PubMed  Google Scholar 

  70. Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GL, Edwards KJ, et al. Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat. 2013;34:57–65.

    CAS  PubMed  Google Scholar 

  71. Piazza R, Ramazzotti D, Spinelli R, Pirola A, De Sano L, Ferrari P, et al. OncoScore: a novel, Internet-based tool to assess the oncogenic potential of genes. Sci Rep. 2017;7:46290.

    PubMed  Google Scholar 

  72. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lane L, Argoud-Puy G, Britan A, Cusin I, Duek PD, Evalet O, et al. neXtProt: a knowledge platform for human proteins. Nucleic Acids Res. 2012;40:D76–83.

    CAS  PubMed  Google Scholar 

  74. Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, et al. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res. 2016;44:D279–85.

    CAS  PubMed  Google Scholar 

  75. Mitchell A, Chang HY, Daugherty L, Fraser M, Hunter S, Lopez R, et al. The InterPro protein families database: the classification resource after 15 years. Nucleic Acids Res. 2015;43:D213–21.

    PubMed  Google Scholar 

  76. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47:D941–7.

    PubMed  Google Scholar 

  77. Losman JA, Kaelin WG Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013;27:836–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    PubMed  PubMed Central  Google Scholar 

  80. Kerkhof J, Schenkel LC, Reilly J, McRobbie S, Aref-Eshghi E, Stuart A, et al. Clinical validation of copy number variant detection from targeted next-generation sequencing panels. J Mol Diagn. 2017;19:905–20.

    CAS  PubMed  Google Scholar 

  81. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767–73.

    CAS  PubMed  Google Scholar 

  82. Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20:1061–6.

    CAS  PubMed  Google Scholar 

  83. Reeser JW, Martin D, Miya J, Kautto EA, Lyon E, Zhu E, et al. Validation of a targeted RNA sequencing assay for kinase fusion detection in solid tumors. J Mol Diagn. 2017;19:682–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Salk JJ, Schmitt MW, Loeb LA. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet. 2018;19:269–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103:2794–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208–15.

    CAS  PubMed  Google Scholar 

  87. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276–83.

    CAS  PubMed  Google Scholar 

  88. Parker WT, Lawrence RM, Ho M, Irwin DL, Scott HS, Hughes TP, et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol. 2011;29:4250–9.

    CAS  PubMed  Google Scholar 

  89. Soverini S, De Benedittis C, Machova Polakova K, Brouckova A, Horner D, Iacono M, et al. Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood. 2013;122:1634–48.

    CAS  PubMed  Google Scholar 

  90. Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, et al. Small molecule inhibitor of CBFβ-RUNX binding for RUNX transcription factor driven cancers. EBioMedicine. 2016;8:117–31.

    PubMed  PubMed Central  Google Scholar 

  91. Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, et al. Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018;131:328–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell. 2015;28:343–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Song C, Gowda C, Pan X, Ding Y, Tong Y, Tan BH, et al. Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood. 2015;126:1813–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pikman Y, Stegmaier K. Targeted therapy for fusion-driven high-risk acute leukemia. Blood. 2018;132:1241–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Dafflon C, Craig VJ, Méreau H, Gräsel J, Schacher Engstler B, Hoffman G, et al. Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia. 2016;31:1269–77.

    PubMed  Google Scholar 

  97. Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, et al. Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice. Science. 2015;347:779–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8:117–355.

    Google Scholar 

  99. Yong ASM, Szydlo RM, Goldman JM, Apperley JF, Melo JV. Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML. Blood. 2006;107:205–12.

    CAS  PubMed  Google Scholar 

  100. McWeeney SK, Pemberton LC, Loriaux MM, Vartanian K, Willis SG, Yochum G, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood. 2010;115:315–25.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Nicola Evans and the International CML Foundation (iCMLf) for facilitating meetings and discussion for preparation of the manuscript. SB receives support from the National Health and Medical Research Council of Australia (APP1104425). DK received research support from the Princess Margaret Cancer Foundation, Toronto, Canada. JFA is a NIHR Senior Investigator and acknowledges the support of the Imperial College NIHR Biomedical Research Centre. SM receives support from the Finnish Cancer Organizations and Gyllenberg Foundation. CC receives funding support from the National Research Foundation Singapore under Clinician Scientist Awards, NMRC/CSA/017/2010 (C.C.) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC); by the Agency for Science, Technology, and Research (A*STAR) Biomedical Research Council Translational Clinical Research Partnership Grant, BMRC/13/1/96/681 (CC); and the Duke–National University of Singapore Signature Research Program funded by the A*STAR and the Ministry of Health, Singapore. BJD receives support from the Howard Hughes Medical Institute. TPH receives support from the National Health and Medical Research Council of Australia (APP1135949) and has the financial support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health.

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Author notes

  1. These authors contributed equally: Susan Branford, Dennis Dong Hwan Kim

Authors and Affiliations

  1. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia

    Susan Branford

  2. School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia

    Susan Branford

  3. School of Medicine, University of Adelaide, Adelaide, Australia

    Susan Branford & Timothy P. Hughes

  4. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada

    Dennis Dong Hwan Kim

  5. Centre for Haematology, Hammersmith Hospital, Imperial College, London, UK

    Jane F. Apperley & Georgios Nteliopoulos

  6. Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA

    Christopher A. Eide & Brian J. Druker

  7. Howard Hughes Medical Institute, Portland, 97239, OR, USA

    Christopher A. Eide & Brian J. Druker

  8. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    Satu Mustjoki

  9. Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland

    Satu Mustjoki

  10. Cancer and Stem Cell Biology Signature Research Program, Duke−NUS Medical School, Singapore, Singapore

    S. Tiong Ong & Charles Chuah

  11. Department of Haematology, Singapore General Hospital, Singapore, Singapore

    S. Tiong Ong & Charles Chuah

  12. Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Thomas Ernst & Andreas Hochhaus

  13. University of Milano Bicocca, San Gerardo Hospital, Monza, Italy

    Carlo Gambacorti-Passerini

  14. Myeloproliferative Neoplasms Program, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael J. Mauro

  15. Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea

    Dong-Wook Kim

  16. Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

    Dong-Wook Kim

  17. Bergonié Cancer Institute, Inserm Unit 916, University of Bordeaux, Bordeaux, France

    Francois-Xavier Mahon

  18. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jorge Cortes

  19. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jerry P. Radich

  20. South Australian Health & Medical Research Institute, Adelaide, Australia

    Timothy P. Hughes

  21. Department of Haematology, SA Pathology, Adelaide, Australia

    Timothy P. Hughes

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  1. Susan Branford
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on behalf of the International CML Foundation Genomics Alliance

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Correspondence to Susan Branford.

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Conflict of interest

SB: Member of the advisory board of Qiagen, Novartis and Bristol-Myers Squibb; Received honoraria from Qiagen, Novartis, Bristol-Myers Squibb and Cepheid. Research support from Novartis. CC: Honorarium from Novartis Oncology, Bristol-Myers Squibb, Korea Otsuka Pharmaceuticals, Chiltern International; Research funding from Bristol-Myers Squibb. BJD: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). TPH: Holds a consultancy role and has received research funding and honoraria from Novartis, Bristol-Myers Squibb and Ariad. Other authors declare that they have no conflict of interest.

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Branford, S., Kim, D.D.H., Apperley, J.F. et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia 33, 1835–1850 (2019). https://doi.org/10.1038/s41375-019-0512-y

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