Acute myeloid leukemia

Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis

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We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.

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  1. 1

    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: 264–278.

  2. 2

    Chen J, Odenike O, Rowley JD . Leukaemogenesis: more than mutant genes. Nat Rev Cancer 2010; 10: 23–36.

  3. 3

    Network TCGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

  4. 4

    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 8 366: 883–892.

  5. 5

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.

  6. 6

    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: 2477–2487.

  7. 7

    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: 1472–1478.

  8. 8

    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126: 9–16.

  9. 9

    Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F et al. Cell of Origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex. Cancer Cell 2011; 20: 39–52.

  10. 10

    Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011; 19: 138–152.

  11. 11

    Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

  12. 12

    Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.

  13. 13

    Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29: 2889–2896.

  14. 14

    Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrozek K et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 2012; 30: 742–750.

  15. 15

    Renneville A, Boissel N, Nibourel O, Berthon C, Helevaut N, Gardin C et al. Prognostic significance of DNA methyltransferase 3 A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 2012; 26: 1247–1254.

  16. 16

    Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

  17. 17

    Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood 2012; 119: 5824–5831.

  18. 18

    Gaidzik VI, Schlenk RF, Paschka P, Stolzle A, Spath D, Kuendgen A et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood 2013; 121: 4769–4777.

  19. 19

    Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

  20. 20

    Heil G, Krauter J, Raghavachar A, Bergmann L, Hoelzer D, Fiedler W et al. Risk-adapted induction and consolidation therapy in adults with de novo AML aged </= 60 years: results of a prospective multicenter trial. Ann Hematol 2004; 83: 336–344.

  21. 21

    Mitelman F . ISCN (1995): an International System for Human Cytogenetic Nomenclature. SKarger: Basel, Switzerland, 1995.

  22. 22

    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

  23. 23

    Korn EL . Censoring distributions as a measure of follow-up in survival analysis. Stat Med 1986; 5: 255–260.

  24. 24

    Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010; 26: 589–595.

  25. 25

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297–1303.

  26. 26

    Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 2014; 25: 442–454.

  27. 27

    Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2012; 44: 23–31.

  28. 28

    Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 2015; 373: 35–47.

  29. 29

    Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015; 518: 552–555.

  30. 30

    Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616–3627, quiz 3699.

  31. 31

    Renneville A, Kaltenbach S, Clappier E, Collette S, Micol JB, Nelken B et al. Wilms tumor 1 (WT1) gene mutations in pediatric T-cell malignancies. Leukemia 2010; 24: 476–480.

  32. 32

    Scourzic L, Couronne L, Pedersen MT, Della Valle V, Diop M, Mylonas E et al. DNMT3A mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice. Leukemia 2016.

  33. 33

    Meyer SE, Qin T, Muench DE, Masuda K, Venkatasubramanian M, Orr E et al. DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia. Cancer Discov 2016; 6: 501–515.

  34. 34

    Couronne L, Bastard C, Bernard OA . TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 2012; 366: 95–96.

  35. 35

    Neumann M, Heesch S, Schlee C, Schwartz S, Gokbuget N, Hoelzer D et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 2013; 121: 4749–4752.

  36. 36

    Huether R, Dong L, Chen X, Wu G, Parker M, Wei L et al. The landscape of somatic mutations in epigenetic regulators across 1000 paediatric cancer genomes. Nat Commun 2014; 5: 3630.

  37. 37

    Thiede C, Bullinger L, Hernández-Rivas JM, Heuser M, Preudhomme C, Best S et al. Results of the ‘Evaluation of NGS in AML-Diagnostics (ELAN)’ Study—an Inter-Laboratory Comparison Performed in 10 European Laboratories ASH Abstract 2014.

  38. 38

    Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

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We are indebted to all the patients and contributing doctors. We thank the staff of the Central Animal Facility and Matthias Ballmaier from the Cell Sorting Core Facility (supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft) of Hannover Medical School, Vishwas Sharma, Michael Morgan, Silke Glowotz, Nicole Ernst and Kerstin Görlich, for their support on this project. This study was supported by the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx), grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung e.V; DFG grant HE 5240/5-1 and HE 5240/6-1 and BU 1339/8-1; an ERC grant under the European Union’s Horizon 2020 research and innovation program (No. 638035) and by grants from Dieter-Schlag Stiftung.

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Correspondence to M Heuser.

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Thol, F., Klesse, S., Köhler, L. et al. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis. Leukemia 31, 1286–1295 (2017) doi:10.1038/leu.2016.345

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