Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease

Iris T. Chan, Jeffery L. Kutok, Ifor R. Williams, Sarah Cohen, Lauren Kelly, Hirokazu Shigematsu, Leisa Johnson, Koichi Akashi, David A. Tuveson, Tyler Jacks, D. Gary Gilliland

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

Oncogenic ras alleles are among the most common mutations found in patients with acute myeloid leukemia (AML). Previously, the role of oncogenic ras in cancer was assessed in model systems overexpressing oncogenic ras from heterologous promoters. However, there is increasing evidence that subtle differences in gene dosage and regulation of gene expression from endogenous promoters play critical roles in cancer pathogenesis. We characterized the role of oncogenic K-ras expressed from its endogenous promoter in the hematopoietic system using a conditional allele and IFN-inducible, Cre-mediated recombination. Mice developed a completely penetrant myeloproliferative syndrome characterized by leukocytosis with normal maturation of myeloid lineage cells; myeloid hyperplasia in bone marrow; and extramedullary hematopoiesis in the spleen and liver. Flow cytometry confirmed the myeloproliferative phenotype. Genotypic and Western blot analysis demonstrated Cre-mediated excision and expression, respectively, of the oncogenic K-ras allele. Bone marrow cells formed growth factor-independent colonies in methylcellulose cultures, but the myeloproliferative disease was not transplantable into secondary recipients. Thus, oncogenic K-ras induces a myeloproliferative disorder but not AML, indicating that additional mutations are required for AML development. This model system will be useful for assessing the contribution of cooperating mutations in AML and testing ras inhibitors in vivo.

Original languageEnglish
Pages (from-to)528-538
Number of pages11
JournalJournal of Clinical Investigation
Volume113
Issue number4
DOIs
Publication statusPublished - Feb 2004
Externally publishedYes

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Chan, I. T., Kutok, J. L., Williams, I. R., Cohen, S., Kelly, L., Shigematsu, H., ... Gilliland, D. G. (2004). Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. Journal of Clinical Investigation, 113(4), 528-538. https://doi.org/10.1172/JCI20476