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HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [RNA-seq]

ABSTRACT: This study identifies HOXA9 protein interactome in acute myeloid leukemia cells. Integrated genomic, transcriptomic and proteomic analyses further demonstrated that the HOXA9-SAFB-chromatin complex associates with NuRD and HP1γ to repress the expression of factors associated with differentiation and apoptosis in leukemia maintenance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221700 | GEO | 2022/12/27

REPOSITORIES: GEO

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HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [CUT&RUN/ChIP-Seq]

Project description:This study identifies HOXA9 protein interactome in acute myeloid leukemia cells. Integrated genomic, transcriptomic and proteomic analyses further demonstrated that the HOXA9-SAFB-chromatin complex associates with NuRD and HP1γ to repress the expression of factors associated with differentiation and apoptosis in leukemia maintenance.

2022-12-27 | GSE221697 | GEO

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

Project description:HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

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HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.

Project description:HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.

| S-EPMC10113176 | biostudies-literature

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [RNA-seq]

Project description:HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [RNA-seq]

| PRJNA915392 | ENA

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [CUT&RUN/ChIP-Seq]

Project description:HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia [CUT&RUN/ChIP-Seq]

| PRJNA915391 | ENA

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

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

2022-12-27 | GSE221701 | GEO

Identification of SAFB and HnrnpU interactors

Project description:Scaffold Attachment Factor B (SAFB) is a conserved RNA Binding Protein (RBP) that is essential for early mammalian development. However, the RNAs that associate with SAFB in mouse embryonic stem cells have not been characterized. Here, we addressed this unknown using RNA-seq and SAFB RNA immunoprecipitation followed by RNA-seq (RIP-seq) in wild-type mouse embryonic stem cells (ESCs) and in ESCs in which SAFB and SAFB2 were knocked out. The transcript most enriched in SAFB association was the lncRNA Malat1, which contains a series of purine-rich motifs in its 5 end. Beyond Malat1, SAFB predominantly associated with introns of protein-coding genes also through purine-rich motifs. Knockout of SAFB/2 led to down- and upregulation of genes in multiple biological pathways. The nascent transcripts of many downregulated genes associated with high levels of SAFB in wild-type cells, implying that SAFB binding promotes the expression of these genes. Reintroduction of SAFB into double-knockout cells restored gene expression towards wild-type levels, an effect that was again observable at the level of nascent transcripts. Proteomic analyses indicate an enrichment of nuclear speckle-associated, SR proteins in FLAG-tagged SAFB immunoprecipitated samples. Comparison to immunoprecipitates made from FLAG-tagging of another nuclear-enriched RNA-binding protein called HNRNPU (also known as SAF-A) identified both similarities and differences. Perhaps most notably, we observed a stronger enrichment for speckle-associated proteins in SAFB immunoprecipitations and a strong enrichment for paraspeckle-associated proteins in HNRNPU immunoprecipitations. Our findings suggest that among other potential functions in mouse embryonic stem cells, SAFB directly promotes the expression of a subset of genes through its ability to bind purine regions in nascent RNA.

2023-07-20 | PXD038103 | Pride

Effect of loss of Jmjd1c on Hoxa9/Meis1 leukemia

Project description:Analysis of gene expression profile of Hoxa9/Meis1 leukemia cells 6 days after loss of Jmjd1c. Loss of Jmjd1c induces differentiation and Hoxa9/Meis1 leukemia cells. These results provide insight into the role of Jmjd1c in AML with elelvated expression of Hoxa9.

2016-06-09 | GSE75580 | GEO

Expression data from murine cell line transduced with epitope tagged forms of Hoxa9

Project description:Importantly increasing evidence shows that Hox genes such as Hoxa9 are key regulators of stem cell self-renewal and hematopoiesis. Hoxa9 is expressed in early hematopoietic progenitor cells and promotes stem cell expansion. In contrast Hoxa9 down regulation is associated with hematopoietic differentiation. In addition to its role in development, HOXA9 has been intensively studied because of its central role in human acute leukemias. Despite their obvious biomedical importance, the mechanisms through which Hoxa9 and its partner proteins exert their downstream functions are poorly understood. Using whole-genome gene expression profiling, we identified direct targets of Hoxa9 in murine MHPs after 4-OHT withdraw, resulting in cell differentiation.

2011-02-01 | GSE21299 | GEO

Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia

Project description:The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feed-forward loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, we show that Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.

2017-06-14 | PXD004192 | Pride

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