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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Borhan R. Saeed
  • Linda Manta
  • Simon Raffel
  • Paul Theodor Pyl
  • Eike C. Buss
  • Wenwen Wang
  • Volker Eckstein
  • Anna Jauch
  • Andreas Trumpp
  • Wolfgang Huber
  • Anthony D. Ho
  • Christoph Lutz
Enheter & grupper
Externa organisationer
  • Heidelberg University
  • German Cancer Research Centre
  • European Molecular Biology Laboratory Heidelberg
  • Fudan University Shanghai Cancer Center (FUSCC)
  • Fudan University
  • Praxis für Hämatologie und Onkologie, Koblenz
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi

Nyckelord

Originalspråkengelska
Sidor (från-till)2825-2838
TidskriftInternational Journal of Cancer
Volym148
Utgåva nummer11
Tidigt onlinedatum2021 jan 7
StatusPublished - 2021
PublikationskategoriForskning
Peer review utfördJa