Rapid development of myeloproliferative neoplasm in mice with Ptpn11D61Y mutation and haploinsufficient for Dnmt3a
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Lisa Deng1,2, Briana M. Richine1,2, Elizabeth L. Virts1,4, Victoria N. Jideonwo-Auman1,4, Rebecca J. Chan1,2,4,5 and Reuben Kapur1,2,3,4
1Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
3Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
4Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
5Gilead Sciences, Inc., Foster City, CA, USA
Reuben Kapur, email: [email protected]
Keywords: AML; JMML; DNMT3A; SHP2; myeloproliferation
Received: November 02, 2017 Accepted: December 08, 2017 Published: December 26, 2017
PTPN11 gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia patients. We studied the combined effect of both Ptpn11 gain-of-function mutation (D61Y) and Dnmt3a haploinsufficiency on mouse hematopoiesis, the presence of which has been described in both juvenile myelomonocytic leukemia and acute myeloid leukemia patients. Double mutant mice rapidly become moribund relative to any of the other genotypes, which is associated with enlargement of the spleen and an increase in white blood cell counts. An increase in the mature myeloid cell compartment as reflected by the presence of Gr1+Mac1+ cells was also observed in double mutant mice relative to any other group. Consistent with these observations, a significant increase in the absolute number of granulocyte macrophage progenitors (GMPs) was seen in double mutant mice. A decrease in the lymphoid compartment including both T and B cells was noted in the double mutant mice. Another significant difference was the presence of extramedullary erythropoiesis with increased erythroid progenitors in the spleens of Dnmt3a+/−;D61Y mice relative to other groups. Taken together, our results suggest that the combined haploinsufficiency of Dnmt3a and presence of an activated Shp2 changes the composition of multiple hematopoietic lineages in mice relative to the individual heterozygosity of these genes.
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