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Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia
Stefan P. Tarnawsky, … , Rebecca J. Chan, Mervin C. Yoder
Stefan P. Tarnawsky, … , Rebecca J. Chan, Mervin C. Yoder
Published November 14, 2017; First published August 28, 2017
Citation Information: J Clin Invest. 2017;127(10):3652-3656. https://doi.org/10.1172/JCI94031.
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Categories: Brief Report Hematology

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

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Abstract

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that bears distinct characteristics associated with abnormal fetal development. JMML has been extensively modeled in mice expressing the oncogenic KrasG12D mutation. However, these models have struggled to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic expression, and the pervasive emergence of T cell acute lymphoblastic leukemia. Here, we have developed a model of JMML using mice that express KrasG12D in multipotent progenitor cells (Flt3Cre+ KrasG12D mice). These mice express KrasG12D in utero, are born at normal Mendelian ratios, develop hepatosplenomegaly, anemia, and thrombocytopenia, and succumb to a rapidly progressing and fully penetrant neonatal myeloid disease. Mutant mice have altered hematopoietic stem and progenitor cell populations in the BM and spleen that are hypersensitive to granulocyte macrophage–CSF due to hyperactive RAS/ERK signaling. Biased differentiation in these progenitors results in an expansion of neutrophils and DCs and a concomitant decrease in T lymphocytes. Flt3Cre+ KrasG12D fetal liver hematopoietic progenitors give rise to a myeloid disease upon transplantation. In summary, we describe a KrasG12D mouse model that reproducibly develops JMML-like disease. This model will prove useful for preclinical drug studies and for elucidating the developmental origins of pediatric neoplasms.

Authors

Stefan P. Tarnawsky, Michihiro Kobayashi, Rebecca J. Chan, Mervin C. Yoder

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Figure 1

Flt3Cre+ KrasG12D mice develop a JMML-like disease.

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Flt3Cre+ KrasG12D mice develop a JMML-like disease.
(A) Weight gain from...
(A) Weight gain from birth (n = 12 mutants and 19 controls). (B) Overall survival (statistical analysis by Mantel-Cox test). (C) Peripheral blood smear (n = 5). Scale bar: 100 μm. (D) Flow cytometric quantification of tissue leukocytes. (E) Seven-day BM colony formation with 100 nM PD0325901 or 0.1% DMSO (n = 3 biological replicates/group). All analyses were performed on 3- to 4-week-old moribund Flt3Cre+ KrasG12D mice and age-matched littermates. *P < 0.05, #P < 0.01, and §P < 0.001, by unpaired, 2-tailed Student’s t test (A, D, and E).
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