Uncovering DDX6 Post-transcriptional Regulation in AML Dormancy

Document Type

Article

Publication Date

2026

JAX Location

JGM

Abstract

Relapse remains a major obstacle in the treatment of acute myeloid leukemia (AML), driven by a subset of leukemic cells that enter a dormant, drug-resistant state and evade chemotherapy. To identify novel molecular regulators of dormancy (quiescence), we conducted a genome-wide CRISPR/Cas9 screen using an mCherry-expressing quiescence reporter system. Loss of DDX6, a DEAD-box RNA helicase, was found to promote quiescence and increase resistance to cytarabine, a common first-line chemotherapy drug for AML. Loss of DDX6-mediated control resulted in derepression of the key cell cycle regulators p57 encoded by CDKN1C and BTG2, leading to increased AML quiescence. Here, we demonstrate that direct binding of DDX6 to the 3′UTRs of target mRNAs is a key mechanism of post-transcriptional repression. We further identify p57 as a functionally important downstream target, as p57 knockout partially rescued the increased dormancy and cytarabine resistance induced by DDX6 loss. Together, these findings establish a DDX6-dependent post-transcriptional regulatory network that regulates chemotherapy response and identify DDX6-regulated pathways as potential therapeutic targets to prevent AML relapse.

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