Cytosine deaminase APOBEC3A sensitizes leukemia cells to inhibition of the DNA replication checkpoint

Abby M. Green, Konstantin Budagyan, Katharina E. Hayer, Morgann A. Reed, Milan R. Savani, Gerald B. Wertheim, Matthew D. Weitzman

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy.

Original languageEnglish
Pages (from-to)4579-4588
Number of pages10
JournalCancer research
Volume77
Issue number17
DOIs
StatePublished - Sep 1 2017

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