Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy‐resistant preleukemic clones
To acquire a better understanding of clonal evolution of acute myeloid leukemia (AML) and to identify the clone(s) responsible for disease recurrence, we have comparatively studied leukemia‐specific mutations by whole‐exome‐sequencing (WES) of both the leukemia and the nonleukemia compartments deriv...
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Published in | International journal of cancer Vol. 148; no. 11; pp. 2825 - 2838 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.06.2021
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | To acquire a better understanding of clonal evolution of acute myeloid leukemia (AML) and to identify the clone(s) responsible for disease recurrence, we have comparatively studied leukemia‐specific mutations by whole‐exome‐sequencing (WES) of both the leukemia and the nonleukemia compartments derived from the bone marrow of AML patients. The T‐lymphocytes, B‐lymphocytes and the functionally normal hematopoietic stem cells (HSC), that is, CD34+/CD38−/ALDH+ cells for AML with rare‐ALDH+ blasts (<1.9% ALDH+ cells) were defined as the nonleukemia compartments. WES identified 62 point‐mutations in the leukemia compartment derived from 12 AML‐patients at the time of diagnosis and 73 mutations in 3 matched relapse cases. Most patients (8/12) showed 4 to 6 point‐mutations per sample at diagnosis. Other than the mutations in the recurrently mutated genes such as DNMT3A, NRAS and KIT, we were able to identify novel point‐mutations that have not yet been described in AML. Some leukemia‐specific mutations and cytogenetic abnormalities including DNMT3A(R882H), EZH2(I146T) and inversion(16) were also detectable in the respective T‐lymphocytes, B‐lymphocytes and HSC in 5/12 patients, suggesting that preleukemia HSC might represent the source of leukemogenesis for these cases. The leukemic evolution was reconstructed for five cases with detectable preleukemia clones, which were tracked in follow‐up and relapse samples. Four of the five patients with detectable preleukemic mutations developed relapse. The presence of leukemia‐specific mutations in these nonleukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long‐term cure.
What's new?
Acute myeloid leukemia (AML) develops and progresses through a multistep process, involving the accumulation of multiple molecular abnormalities over time. Little is known, however, about AML‐inducing mutations and the role of clones in AML evolution and prognosis. Here, using molecular comparison of leukemic and non‐leukemic cells derived from the same bone marrow of AML patients, the authors identified novel point mutations and initiating mutations in AML. Moreover, leukemic evolution was reconstructed from pre‐leukemic clones in five patients, four of whom experienced relapse. The findings provide insight into clonal evolution in AML and could aid the identification of novel therapeutic targets. |
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Bibliography: | Funding information Deutsche Forschungsgemeinschaft, Grant/Award Number: SFB 873; Dietmar Hopp Stiftung ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0020-7136 1097-0215 |
DOI: | 10.1002/ijc.33461 |