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Bamezai, S.* ; Pulikkottil, A.J.* ; Yadav, T.* ; Vegi, N.M.* ; Mueller, J.* ; Mark, J.* ; Mandal, T.* ; Feder, K.* ; Ihme, S.* ; Song, C.* ; Rosler, R.* ; Wiese, S.* ; Hoell, J.I.* ; Kloetgen, A.* ; Karsan, A.* ; Kumari, A.* ; Wojenski, L.* ; Sinha, A.U.* ; González-Menéndez, I.* ; Quintanilla-Martinez, L.* ; Donato, E.* ; Trumpp, A.* ; Kruse, E. ; Hamperl, S. ; Zou, L.* ; Rawat, V.P.S.* ; Buske, C.*

A noncanonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.

Blood 142, 90-105 (2023)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
RNA-binding proteins (RBPs) form a large and diverse class of factors, many members of which are overexpressed in hematologic malignancies. RBPs participate in various processes of messenger RNA (mRNA) metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here, we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in patients with acute myeloid leukemia (AML) and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells. In AML cells, PIWIL4 binds to a small number of known piwi-interacting RNA. Instead, it largely interacts with mRNA annotated to protein-coding genic regions and enhancers that are enriched for genes associated with cancer and human myeloid progenitor gene signatures. PIWIL4 depletion in AML cells downregulates the human myeloid progenitor signature and leukemia stem cell (LSC)-associated genes and upregulates DNA damage signaling. We demonstrate that PIWIL4 is an R-loop resolving enzyme that prevents R-loop accumulation on a subset of AML and LSC-associated genes and maintains their expression. It also prevents DNA damage, replication stress, and activation of the ATR pathway in AML cells. PIWIL4 depletion potentiates sensitivity to pharmacological inhibition of the ATR pathway and creates a pharmacologically actionable dependency in AML cells.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 142, Issue: 1, Pages: 90-105 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epigenetics and Stem Cells (IES)