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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287298 | GEO | 2025/07/24

REPOSITORIES: GEO

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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

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

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

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

| PRJNA1214292 | ENA

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

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

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

A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML

Project description:Acute myeloid leukemia (AML) is characterized by serious aggressivity of high relapse risk and various molecular aberrations. Rearrangements involving NUP98 with multiple fusing partner genes in myeloid malignancies indicate dismal survival outcomes. Mechanisms contributing to subsequent aggressive progression and severe relapse risk of NUP98-rearranged AML remain undefined. Here we identified a novel oncogenic fusion RUNX1/ZNF423 in a relapse and refractory AML patient with NUP98/NSD1. And mice xenografted from the patient bearing both RUNX1/ZNF423 and NUP98/NSD1 display more severe engraftment levels than NUP98/NSD1 only. Mechanically, RUNX1/ZNF423 accompanied with NUP98/NSD1 recapitulated transcriptional signatures in hematopoietic differentiation blockage and altered amino acid metabolism pathway. Moreover, single-cell sequencing confirmed the coexistence of RUNX1/ZNF423 with NUP98/NSD1 in the same leukemic blast. Meanwhile, we also found that the coexistence of gene fusions in NUP98-rearranged AML was a significant phenomenon, which probably contributes to their worse clinical outcome. Finally, tailored intervention treatment based on ex vivo drug sensitivity testing is provided to this relapse and refractory AML patient and achieved favorable clinical response. Taken together, we not only identified a novel gene fusion RUNX1/ZNF423 with transforming potential detected in a NUP98-rearranged AML, but also achieved a deeper understanding into mechanisms contributing to disease relapse in AML.

2024-12-01 | GSE222098 | GEO

A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML [RNAseq]

2024-12-01 | GSE221767 | GEO