Acute myeloid leukemia

Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis

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Abstract

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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Acknowledgements

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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The authors declare no conflict of interest.

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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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