Transcriptomics

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MALAT1 is required for phenotypic consequences of TET2 mutations in myeloid neoplasms.


ABSTRACT: Loss of function mutations inTET2(LOF) occur in up to 58% and 30% of myeloid malignancies and clonal hematopoiesis (CH) respectively. Genetically engineered murine models of Tet2 LOF display splenomegaly, granulomonocytic expansion, and increased bone marrow hematopoietic stem and progenitors. However, the direct downstream effectors of TET2 LOF leading to this phenotype are unknown. Using multiome single cell sequencing from a cohort of severe COVID patients with or without TET2 mutations we show that MALAT1, a therapeutically tractable long non-coding RNA, is overexpressed and is both necessary and sufficient to induce TET2 LOF phenotypes. We additionally demonstrate that TET2 LOF leads to decrease activity of the transcriptional repressor EGR1 leading to upregulation of MALAT1. This upregulation then leads to sustained NFkB activity by inhibiting the phosphatase activity of PP2A on P65 resulting in increased pro-inflammatory cytokines such as IL-6 required for TET2 LOF phenotypes in MALAT1 overexpressing mice

ORGANISM(S): Mus musculus

PROVIDER: GSE243492 | GEO | 2024/08/13

REPOSITORIES: GEO

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