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

Autor:	Rajagopalan A; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Feng Y; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Gayatri MB; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Ranheim EA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Klungness T; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Matson DR; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Lee MH; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Jung MM; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.; Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Zhou Y; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Gao X; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA., Nadiminti KV; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.; Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA., Yang DT; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Tran VL; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.; Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Padron E; Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, Florida, USA., Miyamoto S; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Bresnick EH; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.; Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Zhang J; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Dec 15; Vol. 133 (24). Date of Electronic Publication: 2023 Dec 15.
DOI:	10.1172/JCI173116
Abstrakt:	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.
Databáze:	MEDLINE
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