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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221767 | GEO | 2024/12/01

REPOSITORIES: GEO

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Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.

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

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