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

Stefan P. Tarnawsky, Rebecca J. Chan, Rebecca Chan

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3652-3656
Number of pages5
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

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Juvenile Myelomonocytic Leukemia
Myeloid Leukemia
Hematopoietic Stem Cells
Infant, Newborn, Diseases
Pediatrics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Fetal Development
Granulocytes
Thrombocytopenia
Anemia
Neoplasms
Neutrophils
Stem Cells
Spleen
Transplantation
Macrophages
T-Lymphocytes
Mutation
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

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Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia. / Tarnawsky, Stefan P.; Chan, Rebecca J.; Chan, Rebecca.

In: Journal of Clinical Investigation, Vol. 127, No. 10, 02.10.2017, p. 3652-3656.

Research output: Contribution to journalArticle

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