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Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE150428 | GEO | 2021/01/14

REPOSITORIES: GEO

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ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.

Project description:Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

| S-EPMC7886901 | biostudies-literature

Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (RNA-seq)

Project description:The recurring t(10;17)(p15;q21) chromosomal translocation as detected in a subset of human acute myeloid leukemia (AML) patients produces an aberrant fusion gene ZMYND11-MBTD1 (ZM), the biological consequence of which, however, remains elusive. Here we show that ZM chimera confers primary murine hematopoietic stem/progenitor cells (HSPCs) an indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics analyses revealed that ZM directly binds to and maintains high expression of pro-leukemic transcription factor (TF) genes such as Hox, Meis1, Myc, Myb, and Sox4. Mechanistically, ZM interacts with and recruits the Tip60 acetyltransferase complex, both of which occupy promoter-proximal genomic regions that are enriched with histone acetylation and devoid of H3K27me3. Furthermore, systematic mutagenesis of ZM revealed an essential requirement of Tip60 association and an H3K36me3-binding PWWP domain for leukemic transformation and proto-oncogene activation. Finally, inhibitor of histone acetylation-‘reading’ bromodomain proteins is efficacious in treating ZM-induced AML. Collectively, this study demonstrated the AML-causing effect of ZM chimera with relevant animal models, examined into its gene-regulatory functions and protein interactome, and reports a promising mechanism-based therapeutic strategy.

2021-01-14 | GSE150424 | GEO

Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (ChIP-seq)

2021-01-14 | GSE149782 | GEO

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Project description:Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, c-Myc and Sox4. Mechanistically, ZM recruits NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of TIP60 interaction and an H3K36me3-binding PWWP domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

2021-01-14 | GSE161656 | GEO

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Project description:Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

2021-01-21 | PXD023702 | Pride

Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism

Project description:Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism

| PRJNA632021 | ENA

Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (ChIP-seq)

Project description:Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (ChIP-seq)

| PRJNA630151 | ENA

Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (RNA-seq)

Project description:Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (RNA-seq)

| PRJNA632013 | ENA

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Project description:ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

| PRJNA679040 | ENA

Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

Project description:In this study, we characterize the fusion protein produced by the ZMYND11-MBTD1 translocation in acute myeloid leukemia. We express the fusion protein and necessary controls in K562 Cells. The fusion protein assembles ZMYND11 factor with the full acetyltransferase NuA4/TIP60 complex. The fusion protein leads to mislocalization NuA4/TIP60 complex in gene bodies, thereby increasing H4ac in specific gene targets. Finally, chromatin aberration is linked to aberrant gene expression and spliced isoforms.

2022-06-01 | GSE171673 | GEO

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