p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia.
Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous NrasG12D/+in AML, we generated conditional NrasG12D/+p53-/-mice. Consistent with the clinical data, recipient mice transplanted with NrasG12D/+p53-/-bone marrow cells rapidly develop a highly penetrant AML. We find that p53-/-cooperates with NrasG12D/+to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). NrasG12D/+p53-/-MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53-/-synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML.
McArdle Laboratory for Cancer Research.
Jingfang
J
Zhang
McArdle Laboratory for Cancer Research.
Guangyao
G
Kong
Cellular and Molecular Biology Program, and.
Adhithi
A
Rajagopalan
Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI.
Li
L
Lu
Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL.
Jingming
J
Song
Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL.
Mohamed
M
Hussaini
BioInfoRx, Inc., Madison, WI.
Xinmin
X
Zhang
Department of Pathology and Laboratory Medicine and.
Erik A
EA
Ranheim
McArdle Laboratory for Cancer Research.
Yangang
Y
Liu
McArdle Laboratory for Cancer Research.
Jinyong
J
Wang
Department of Cell and Regenerative Biology, University of Wisconsin-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Xin
X
Gao
McArdle Laboratory for Cancer Research.
Yuan-I
YI
Chang
Department of Cell and Regenerative Biology, University of Wisconsin-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Kirby D
KD
Johnson
McArdle Laboratory for Cancer Research.
Yun
Y
Zhou
Department of Pathology and Laboratory Medicine and.
David
D
Yang
Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH; and.
Bhavana
B
Bhatnagar
Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH; and.
David M
DM
Lucas
Department of Cell and Regenerative Biology, University of Wisconsin-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Emery H
EH
Bresnick
Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI.
Xuehua
X
Zhong
Malignant Hematology, Moffitt Cancer Center, Tampa, FL.
Eric
E
Padron
McArdle Laboratory for Cancer Research.
Jing
J
Zhang
D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human