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Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia

ABSTRACT: Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia

PROVIDER: PRJNA1214292 | ENA |

REPOSITORIES: ENA

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Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [RNA-seq]

Project description:This series of expression data aims to investigate transcriptional profiling of cell lines or cord blood CD34+ cells transduced with various NUP98 fusion oncoproteins with or without cooperating alterations of RB1 loss or WT1 frameshift alterationss and menin inhibition with revumenib treatment.

2025-07-24 | GSE287297 | GEO

Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [CUT&RUN]

Project description:Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [CUT&RUN]

| PRJNA1212058 | ENA

Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [RNA-seq]

Project description:Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [RNA-seq]

| PRJNA1212059 | ENA

Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia [CUT&RUN]

Project description:This series CUT&RUN data aims to investigate epigenetic profiling of primary leukemia samples, cell lines, or cord blood CD34+ cells transduced with various NUP98 fusion oncoproteins.

2025-07-24 | GSE287298 | GEO

Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia

Project description:This series of single cell RNA sequencing data aims to investigate the heterogeneity of cellular hieararchies among pediatric acute myeloid leukemia and acute lymphoblastic leukemia with NUP98-rearrangement.

2025-07-24 | GSE287716 | GEO

Fusion oncoproteins and cooperating mutations define disease phenotypes in <i>NUP98</i>-rearranged leukemia.

Project description:Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes correlated to fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177 NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the same NUP98 fusions, such as NUP98::KDM5A acute megakaryocytic leukemia with RB1 loss or T-cell acute lymphoblastic leukemia with NOTCH1 mutations. CUT&RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Using in vitro models, we show RB1 loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas WT1 frameshifts skew differentiation toward dormant lympho-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells. NUP98::KDM5A models with RB1 or WT1 alterations have different sensitivities to menin inhibition, suggesting cellular differentiation stage-specific resistant mechanism against menin inhibitors with clinical implications for NUP98-rearranged leukemia.

| S-EPMC11838931 | biostudies-literature

The Histone Acetyltransferase MOZ is a Molecular Dependency and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia

Project description:NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML), and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that histone acetyltransferase (HAT) complex proteins including MOZ associate with NUP98 FOs, and that BRPF1, an epigenetic writer that associates with MOZ is a molecular dependency in NUP98::KDM5A AML. Inactivation of Brpf1 as well as HAT complex member Moz, Hbo1, Brd1 or Meaf6 in Nup98::Kdm5a;Vav-Cre cells impaired fitness of NUP98-rearranged cells. MOZ inhibition decreased global H3K23ac levels, displaced FO from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ inhibition decreased leukemic burden in multiple NUP98-rearranged leukemia xenograft models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs. SIGNIFICANCE STATEMENT MOZ is a member of NUP98 FO condensates with key roles in leukemia phenotypes. MOZ inhibition is effective in multiple preclinical models, including those non-responsive to Menin inhibition. MOZ and Menin inhibition are synergistic in some NUP98-rearranged models, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.

2025-06-03 | PXD058286 | Pride

The histone acetyltransferase MOZ is a molecular dependency and therapeutic target in NUP98-rearranged acute myeloid leukemia [WGS, ATACseq, CUT&RUN, scRNAseq]

Project description:NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML), and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that histone acetyltransferase (HAT) complex proteins including MOZ associate with NUP98 FOs, and that BRPF1, an epigenetic writer that associates with MOZ, is a molecular dependency in NUP98::KDM5A AML. Inactivation of Brpf1 as well as HAT complex member Moz, Hbo1, Brd1 or Meaf6 in Nup98::Kdm5a;Vav-Cre cells impaired fitness of NUP98-rearranged cells. MOZ acetyltransferase inhibition decreased global H3K23ac levels, displaced FO from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ inhibition decreased leukemic burden in multiple NUP98-rearranged leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs.

2025-06-02 | GSE283096 | GEO

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia [RNA-Seq]

Project description:NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.

2025-06-02 | GSE283531 | GEO

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia [ChIP-Seq]

2025-06-02 | GSE283530 | GEO