4.8 Article

DUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia

Journal

SCIENCE ADVANCES
Volume 9, Issue 37, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.adi3771

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Translocations producing rearranged versions of DUX4-r are a common cause of B-cell acute lymphoblastic leukemia. Our study reveals that DUX4-r has both loss-of-function and gain-of-function effects, leading to leukemia. Understanding the molecular mechanism behind DUX4-r's leukemogenic activity provides potential therapeutic options for this B-ALL subtype.
Translocations producing rearranged versions of the transcription factor double homeobox 4 (DUX4-r) are one of the most frequent causes of B cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wild-type DUX4 but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown, and no targeted therapy is currently available. We found that the rearrangement leads to both a loss and a gain of function in DUX4-r. Loss of CBP/EP300 transcriptional coactivator interaction leads to an inability to bind and activate repressed chromatin. Concurrently, a gain of interaction with the general transcription factor 2 I (GTF2I) redirects DUX4-r toward leukemogenic targets. This neomorphic activity exposes an Achilles' heel whereby DUX4-r-positive leukemia cells are exquisitely sensitive to GTF2I targeting, which inhibits DUX4-r leukemogenic activity. Our work elucidates the molecular mechanism through which DUX4-r causes leukemia and suggests a possible therapeutic avenue tailored to this B-ALL subtype.

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