Recurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining

Tzah Feldman, Akhiad Bercovich, Yoni Moskovitz, Noa Chapal-Ilani, Amanda Mitchell, Jessie J.F. Medeiros, Tamir Biezuner, Nathali Kaushansky, Mark D. Minden, Vikas Gupta, Michael Milyavsky, Zvi Livneh, Amos Tanay, Liran I. Shlush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The mutational mechanisms underlying recurrent deletions in clonal hematopoiesis are not entirely clear. In the current study we inspect the genomic regions around recurrent deletions in myeloid malignancies, and identify microhomology-based signatures in CALR, ASXL1 and SRSF2 loci. We demonstrate that these deletions are the result of double stand break repair by a PARP1 dependent microhomology-mediated end joining (MMEJ) pathway. Importantly, we provide evidence that these recurrent deletions originate in pre-leukemic stem cells. While DNA polymerase theta (POLQ) is considered a key component in MMEJ repair, we provide evidence that pre-leukemic MMEJ (preL-MMEJ) deletions can be generated in POLQ knockout cells. In contrast, aphidicolin (an inhibitor of replicative polymerases and replication) treatment resulted in a significant reduction in preL-MMEJ. Altogether, our data indicate an association between POLQ independent MMEJ and clonal hematopoiesis and elucidate mutational mechanisms involved in the very first steps of leukemia evolution.

Original languageEnglish
Article number2455
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 1 Dec 2021

Funding

FundersFunder number
Applebaum Foundation
ISF-IPMP-Israel3165/ 19, BIRAX 713023
Leukemia and Other Blood Disorders
Sagol Institute for Longevity Research
Horizon 2020 Framework Programme
Israel Science Foundation
Horizon 2020RTF6005-19, ISF-NSFC 2427/18, 714731
Horizon 2020
Rising Tide Foundation

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