Journal Article

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

Gao, Xin, Rajagopalan, Adhithi, Padron, Eric, Tran, Vu L., Miyamoto, Shigeki, Gayatri, Meher B., Ranheim, Erik A., Lee, Moon Hee, Matson, Daniel R., Zhang, Jing, Feng, Yubin, Nadiminti, Kalyan V.G., Zhou, Yun, Bresnick, Emery H., Klungness, Taylor, Jung, Mabel Minji, Yang, David T.

2023

Overview

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

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Gene expression / Gene mutations / Health aspects / Hematology / Hematopoietic stem cells / RNA sequencing / Transplantation