TY - JOUR
T1 - Mdm2/p53 levels in bone marrow mesenchymal stromal cells are essential for maintaining the hematopoietic niche in response to DNA damage
AU - Pourebrahim, Rasoul
AU - Heinz Montoya, Rafael
AU - Alaniz, Zoe
AU - Ostermann, Lauren
AU - Lin, Patrick P.
AU - Liu, Bin
AU - Ayoub, Edward
AU - Burks, Jared K.
AU - Andreeff, Michael
N1 - Funding Information:
We sincerely thank the staff of the Animal Facility, Wendy Schober and Nalini Patel, in the Flow Cytometry Core, Kiersten Maldonado in the Imaging Facility. We also thank Gigi Lozano for providing Mdm2-flox mice. This work was funded by Haas chair in Genetics (to MA), CPRIT MIRA (to MA), Leukemia SPORE (to MA), SPORE Career Enhancement Award (to RP), and TRIUMPH fellowship (to EA). Editorial support was provided by Bryan Tutt, Scientific Editor, Research Medical Library. This research was performed in the Flow Cytometry and Cellular Imaging Core Facility, which is supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant P30CA016672.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for the maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo. We demonstrate that Mdm2 is essential for the emergence, maintenance, and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress–associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC–mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is.
AB - Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for the maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo. We demonstrate that Mdm2 is essential for the emergence, maintenance, and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress–associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC–mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is.
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U2 - 10.1038/s41419-023-05844-7
DO - 10.1038/s41419-023-05844-7
M3 - Article
C2 - 37353528
AN - SCOPUS:85162768065
SN - 2041-4889
VL - 14
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 6
M1 - 371
ER -