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A gain-of-function p53 mutant synergizes with oncogenic Nras to promote acute myeloid leukemia in mice

ABSTRACT: We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have extremely poor prognosis, and most of these TP53 mutations are missense mutations. Here, we report that in contrast to mixed AML and T-cell malignancy developed in NrasG12D/+; p53-/- (NP-/-) mice, NrasG12D/+; p53R172H/+ (NPmut) mice rapidly developed an inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and largely normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that NrasG12D signaling and p53mut synergize to establish an NPmut-AML transcriptome distinct from that of NA-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated expression of inflammatory genes, including those linked to NFΚB signaling. NFΚB was also upregulated in human NRAS;TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NFΚB inhibition in vitro. The proteasome inhibitor bortezomib stabilized NFΚB inhibitory protein IΚBɑ mitigated inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergizes with NrasG12D to promote AML through mechanisms distinct from p53 loss.

ORGANISM(S): Mus musculus

PROVIDER: GSE243642 | GEO | 2023/09/25

REPOSITORIES: GEO

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Acute myeloid leukemia with CEBPA double-mutations harbors in 76.8% of cases concomitant molecular mutations with TET2 and GATA2 alterations demonstrating strong prognostic impact

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