Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones. / Saeed, Borhan R.; Manta, Linda; Raffel, Simon; Pyl, Paul Theodor; Buss, Eike C.; Wang, Wenwen; Eckstein, Volker; Jauch, Anna; Trumpp, Andreas; Huber, Wolfgang; Ho, Anthony D.; Lutz, Christoph.

I: International Journal of Cancer, Vol. 148, Nr. 11, 2021, s. 2825-2838.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Saeed, BR, Manta, L, Raffel, S, Pyl, PT, Buss, EC, Wang, W, Eckstein, V, Jauch, A, Trumpp, A, Huber, W, Ho, AD & Lutz, C 2021, 'Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones', International Journal of Cancer, vol. 148, nr. 11, s. 2825-2838. https://doi.org/10.1002/ijc.33461

APA

Saeed, B. R., Manta, L., Raffel, S., Pyl, P. T., Buss, E. C., Wang, W., Eckstein, V., Jauch, A., Trumpp, A., Huber, W., Ho, A. D., & Lutz, C. (2021). Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones. International Journal of Cancer, 148(11), 2825-2838. https://doi.org/10.1002/ijc.33461

CBE

MLA

Vancouver

Author

Saeed, Borhan R. ; Manta, Linda ; Raffel, Simon ; Pyl, Paul Theodor ; Buss, Eike C. ; Wang, Wenwen ; Eckstein, Volker ; Jauch, Anna ; Trumpp, Andreas ; Huber, Wolfgang ; Ho, Anthony D. ; Lutz, Christoph. / Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones. I: International Journal of Cancer. 2021 ; Vol. 148, Nr. 11. s. 2825-2838.

RIS

TY - JOUR

T1 - Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones

AU - Saeed, Borhan R.

AU - Manta, Linda

AU - Raffel, Simon

AU - Pyl, Paul Theodor

AU - Buss, Eike C.

AU - Wang, Wenwen

AU - Eckstein, Volker

AU - Jauch, Anna

AU - Trumpp, Andreas

AU - Huber, Wolfgang

AU - Ho, Anthony D.

AU - Lutz, Christoph

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - acute myeloid leukemia (AML)

KW - clonal evolution

KW - hematopoietic stem cells (HSC)

KW - relapse

U2 - 10.1002/ijc.33461

DO - 10.1002/ijc.33461

M3 - Article

C2 - 33411954

AN - SCOPUS:85099484018

VL - 148

SP - 2825

EP - 2838

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 11

ER -