A gain-of-function p53 mutant synergizes with oncogenic Nras to promote acute myeloid leukemia in mice
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 NF?B signaling. NF?B 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 NF?B inhibition in vitro. The proteasome inhibitor bortezomib stabilized NF?B inhibitory protein I?B? 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. Overall design: To investigate how mutant p53 cooperates with oncogenic Nras to promote leukemogenesis, we performed RNA-Seq with sorted Lin- cKit+ bone marrow HSPCs from moribund double mutant [NPmut] (n=4) as well as poly I:C treated, age-matched control (n=3), p53 mutant (n=3), and oncogenic Nras (n=3) mice.