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

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...

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Bibliographic Details
Published in:	Nature communications Vol. 12; no. 1; pp. 2455 - 15
Main Authors:	Feldman, Tzah, Bercovich, Akhiad, Moskovitz, Yoni, Chapal-Ilani, Noa, Mitchell, Amanda, Medeiros, Jessie J. F., Biezuner, Tamir, Kaushansky, Nathali, Minden, Mark D., Gupta, Vikas, Milyavsky, Michael, Livneh, Zvi, Tanay, Amos, Shlush, Liran I.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28.04.2021 Nature Publishing Group Nature Portfolio
Subjects:	38 38/39 45 45/100 45/23 45/41 631/208/4041/3196 631/337/1427 631/67/1990/283 631/67/69 Aphidicolin Aphidicolin - pharmacology Calreticulin - genetics Cancer Clonal Hematopoiesis - genetics DNA Breaks, Double-Stranded DNA End-Joining Repair - genetics DNA polymerase DNA Polymerase theta DNA-directed DNA polymerase DNA-Directed DNA Polymerase - drug effects DNA-Directed DNA Polymerase - genetics Enzyme Inhibitors - pharmacology Genes Health care networks Hematology Hematopoiesis Humanities and Social Sciences Humans Leukemia Leukemia, Myeloid - genetics multidisciplinary Mutation Myeloid Progenitor Cells Poly (ADP-Ribose) Polymerase-1 - metabolism Poly(ADP-ribose) polymerase Repair Repressor Proteins - genetics Science Science (multidisciplinary) Sequence Deletion - genetics Serine-Arginine Splicing Factors - genetics Stem cells Tumors
ISSN:	2041-1723, 2041-1723
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Summary:	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. The mutational mechanisms that produce insertions and deletions that lead to clonal hematopoiesis are poorly understood. Here the authors show evidence that frequent deletions that are relevant to myeloid malignancies could be produced by PARP1-dependent microhomology-mediated end joining.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-22803-y