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A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice
Adhithi Rajagopalan, … , Emery H. Bresnick, Jing Zhang
Adhithi Rajagopalan, … , Emery H. Bresnick, Jing Zhang
Published October 17, 2023
Citation Information: J Clin Invest. 2023;133(24):e173116. https://doi.org/10.1172/JCI173116.
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Research Article Hematology Article has an altmetric score of 11

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

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Abstract

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.

Authors

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

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Figure 1

NPmut mice rapidly develop lethal AML.

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NPmut mice rapidly develop lethal AML.
(A) Transgenic mouse lines and il...
(A) Transgenic mouse lines and illustration of the Mx1-Cre induction scheme. (B) Genotyping of p53 and Nras alleles in non–pl-pC–injected NPmut and pI-pC–injected p53mut (Pmut) and NrasG12D BM cells. WBM, whole bone marrow. (C) Kaplan-Meier survival curves of all 4 groups of mice. (D) Disease incidence in moribund p53mut, NrasG12D, and NPmut mice. (E) Quantification of SP weight and H&E-stained SP sections to show monocytic leukemia cells. Original magnification, ×1 (top panel), ×40 (inset). (F) Quantification of liver/body weight and representative image of gross liver morphology. (G) Quantification of monocytes (Mac1+Gr1–), myeloid precursors (Mac1+Gr1mid), and neutrophils (Mac1+Gr1hi) in BM, SP, and PB. (E–G) Results are presented as the mean ± SD. (H) Kaplan-Meier survival curves of recipient mice transplanted with BM cells from 6-week-old NPmut mice and with NPmut AML cells from 3 representative donors. *P < 0.05, **P < 0.01, and ****P < 0.0001, by log-rank test followed by Benjamini-Hochberg multiple-comparison analysis (C and H), 1-way ANOVA followed by Tukey’s post hoc test (E and F), and unpaired, 2-tailed Student’s t test (G). Con, control.

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