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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228474 | GEO | 2023/09/15

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC10881058 | biostudies-literature

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

Project description: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.

2023-09-16 | PXD041273 | Pride

DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [CUT&Tag]

2023-09-15 | GSE228473 | GEO

DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [RNA-seq]

2023-09-15 | GSE227982 | GEO

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

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

| PRJNA949995 | ENA

DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [RNA-seq]

Project description:DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [RNA-seq]

| PRJNA947621 | ENA

DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [CUT&Tag]

Project description:DUX4-r neomorphic activity depending on GTF2I in acute lymphoblastic leukemia [CUT&Tag]

| PRJNA950006 | ENA

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Project description:Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.

| S-EPMC5144107 | biostudies-literature

Transcriptional activities of DUX4 fusions in B-cell acute lymphoblastic leukemia.

Project description: Not available

| S-EPMC6278971 | biostudies-literature

Allelic specificity of IGH-DUX4 translocation in acute lymphoblastic leukemia (ALL)

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-05-08 | GSE115494 | GEO