Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones
(2021) In International Journal of Cancer 148(11). p.2825-2838- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021-01-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- acute myeloid leukemia (AML), clonal evolution, hematopoietic stem cells (HSC), relapse
- in
- International Journal of Cancer
- volume
- 148
- issue
- 11
- pages
- 2825 - 2838
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:85099484018
- pmid:33411954
- ISSN
- 0020-7136
- DOI
- 10.1002/ijc.33461
- language
- English
- LU publication?
- yes
- id
- 1e308175-c529-4304-8204-aef3eaa3617e
- date added to LUP
- 2021-01-29 11:47:28
- date last changed
- 2024-06-27 07:51:26
@article{1e308175-c529-4304-8204-aef3eaa3617e,
abstract = {{<p>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<sup>+</sup>/CD38<sup>−</sup>/ALDH<sup>+</sup> cells for AML with rare-ALDH<sup>+</sup> blasts (<1.9% ALDH<sup>+</sup> 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.</p>}},
author = {{Saeed, Borhan R. and Manta, Linda and Raffel, Simon and Pyl, Paul Theodor and Buss, Eike C. and Wang, Wenwen and Eckstein, Volker and Jauch, Anna and Trumpp, Andreas and Huber, Wolfgang and Ho, Anthony D. and Lutz, Christoph}},
issn = {{0020-7136}},
keywords = {{acute myeloid leukemia (AML); clonal evolution; hematopoietic stem cells (HSC); relapse}},
language = {{eng}},
month = {{01}},
number = {{11}},
pages = {{2825--2838}},
publisher = {{John Wiley & Sons Inc.}},
series = {{International Journal of Cancer}},
title = {{Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones}},
url = {{http://dx.doi.org/10.1002/ijc.33461}},
doi = {{10.1002/ijc.33461}},
volume = {{148}},
year = {{2021}},
}