Oncogenic K-ras cooperates with PML-RARα to induce an acute promyelocytic leukemia-like disease

Iris T. Chan, Jeffery L. Kutok, Ifor R. Williams, Sarah Cohen, Sandra Moore, Hirokazu Shigematsu, Timothy J. Ley, Koichi Akashi, Michelle M. Le Beau, D. Gary Gilliland

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Most patients with acute promyelocytic leukemia (APL) express PML-RARα, the fusion product of t(15;17)(q22;q11.2). Transgenic mice expressing PML-RARα develop APL with long latency, low penetrance, and acquired cytogenetic abnormalities. Based on observations that 4% to 10% of APL patients harbor oncogenic ras mutations, we coexpressed oncogenic K-ras from its endogenous promoter with PML-RARα to generate a short-latency, highly penetrant mouse model of APL. The APL disease was characterized by splenomegaly, leukocytosis, extramedullary hematopoiesis (EMH) in spleen and liver with an increased proportion of immature myeloperoxidase-expressing myeloid forms; transplantability to secondary recipients; and lack of cytogenetic abnormalities. Bone marrow cells showed enhanced self-renewal in vitro. This model establishes a role for oncogenic ras in leukemia pathogenesis and thus validates the oncogenic RAS signaling pathway as a potential target for therapeutic inhibition in leukemia patients. This mouse model should be useful for investigating signaling pathways that promote self-renewal in APL and for testing the in vivo efficacy of RAS signaling pathway inhibitors in conjunction with other targeted therapies such as ATRA (all trans retinoic acid) and arsenic trioxide.

Original languageEnglish
Pages (from-to)1708-1715
Number of pages8
JournalBlood
Volume108
Issue number5
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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    Chan, I. T., Kutok, J. L., Williams, I. R., Cohen, S., Moore, S., Shigematsu, H., Ley, T. J., Akashi, K., Le Beau, M. M., & Gary Gilliland, D. (2006). Oncogenic K-ras cooperates with PML-RARα to induce an acute promyelocytic leukemia-like disease. Blood, 108(5), 1708-1715. https://doi.org/10.1182/blood-2006-04-015040