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

• Published in: The Journal of clinical investigation 2023-12, Vol.133 (24), p.1-12
• Main Authors: Rajagopalan, Adhithi, Feng, Yubin, Cayatri, Meher B, Ranheim, Erik A, Klungness, Taylor, Matson, Daniel R, Lee, Moon Hee, Jung, Mabel Minji, Zhou, Yun, Gao, Xin, Nadiminti, Kalyan VG, Yang, David T, Tran, Vu L, Padron, Eric, Miyamoto, Shigeki, Bresnick, Emery H, Zhang, Jing
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Biomedical research; Bortezomib; Cell growth; Cell proliferation; Cooperation; Gene expression; Hematopoietic stem cells; Hemopoiesis; Inflammation; Leukemia; Lymphocytes; Lymphocytes T; Lymphopoiesis; Malignancy; Medical prognosis; MEK inhibitors; Missense mutation; Mutants; Mutation; Myelopoiesis; Neutrophils; NF-κB protein; p53 Protein; Progenitor cells; Proteasome inhibitors; Proteasomes; Radiation therapy; Targeted cancer therapy; Transcription factors; Transcriptomes; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI173116.

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TPS3 mutations have an extremely poor prognosis and that most of these TPS3 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12/+ p53-/- (NP-/-) mice, NrasGl2D/+ p53Rl72H/+ (NPmut) mice rapidly developed inflammation-associated AML. Underthe 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_κB cells. The NPmut-AML transcriptome showed GATA2 down regulation and elevated the expression of inflammatory genes, indudingthose linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmutKY821 AML cells down regulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEKand NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB-inhibitory protein IkBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmutmice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from pS3 loss.