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 and Liran I. Shlush ()
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Tzah Feldman: Weizmann Institute of Science
Akhiad Bercovich: Weizmann Institute of Science
Yoni Moskovitz: Weizmann Institute of Science
Noa Chapal-Ilani: Weizmann Institute of Science
Amanda Mitchell: University Health Network (UHN)
Jessie J. F. Medeiros: University Health Network (UHN)
Tamir Biezuner: Weizmann Institute of Science
Nathali Kaushansky: Weizmann Institute of Science
Mark D. Minden: University Health Network (UHN)
Vikas Gupta: University Health Network (UHN)
Michael Milyavsky: Tel-Aviv University
Zvi Livneh: Weizmann Institute of Science
Amos Tanay: Weizmann Institute of Science
Liran I. Shlush: Weizmann Institute of Science

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22803-y

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