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.
|State||Published - 1 Dec 2021|
Bibliographical noteFunding Information:
The authors wish to thank Prof. John Dick, and Dr. Ayal Hendel for fruitful discussion and support. All primary patient samples that were used in this study were generously provided by Dr. Mark Minden and through the Leukemia Tissue Bank at Princess Margaret Cancer Centre/ University Health Network. L.S. is the incumbent of The Ruth and Louis Leland career development chair. This research was supported by the EU horizon 2020 grant project MAMLE ID: 714731, LLS and rising tide foundation Grant ID: RTF6005-19, ISF-NSFC 2427/18, ISF-IPMP-Israel Precision Medicine Program 3165/ 19, BIRAX 713023, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, awarded to LIS. LIS is an incumbent of the Ruth and Louis Leland career development chair. N.K. is an incumbent of the Applebaum Foundation Research Fellow Chair. This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Rising Tide Foundation and the Applebaum Foundation.
© 2021, The Author(s).