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

J Clin Invest. 2017 Oct 2;127(10):3652-3656. doi: 10.1172/JCI94031. Epub 2017 Aug 28.

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.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Hematopoietic Stem Cells* / metabolism
  • Hematopoietic Stem Cells* / pathology
  • Leukemia, Myelomonocytic, Juvenile* / metabolism
  • Leukemia, Myelomonocytic, Juvenile* / pathology
  • Mice
  • Mice, Mutant Strains
  • Mutation, Missense*
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Spleen / metabolism
  • Spleen / pathology

Substances

  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)