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

ABSTRACT: Translocations producing rearranged versions of the transcription factor DUX4 (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 wt 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 co-activators interaction and inability to bind and activate repressed chromatin. Gain of interaction with the transcription factor GTF2I, which redirects DUX4-r toward leukemogenic targets. Importantly, 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 suggest a possible therapeutic avenue tailored to this B-ALL subtype.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Bone Marrow

SUBMITTER: Davide Gabellini

LAB HEAD: Davide Gabellini

PROVIDER: PXD041273 | Pride | 2023-09-16

REPOSITORIES: Pride

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