Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model

Masayuki Iwasaki, Takeshi Kuwata, Yukari Yamazaki, Nancy A. Jenkins, Neal G. Copeland, Motomi Osato, Yoshiaki Ito, Evert Kroon, Guy Sauvageau, Takuro Nakamura

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

The chromosomal translocation t(7; 11)(p15;p15), observed in human myeloid leukemia, results in a NUP98 and HOXA9 gene fusion. We generated a transgenic mouse line that specifically expressed the chimeric NUP98-HOXA9 gene in the myeloid lineage. While only 20% of the transgenic mice progressed to leukemia after a latency period, myeloid progenitor cells from nonleukemic transgenic mice still exhibited increased proliferative potential. This suggested that the NUP98-HOXA9 fusion induced a preleukemic phase, and other factors were required for complete leukemogenesis. NUP98-HOX49 expression promoted the onset of retrovirus-induced BXH2 myeloid leukemia. This phenomenon was used to identify cooperative disease genes as common integration sites (CISs). Meis1, a known HOX cofactor, was identified as a CIS with a higher integration frequency in transgenic than in wild-type BXH2 mice. By the same means we identified further 4 candidate cooperative genes, Dnalc4, Fcgr2b, Fcrl, and Con1. These genes cooperated with NUP98-HOXA9 in transforming NIH 3T3 cells. The system described here is a powerful tool to identify cooperative oncogenes and will assist in the clarification of the multistep process of carcinogenesis.

Original languageEnglish (US)
Pages (from-to)784-793
Number of pages10
JournalBlood
Volume105
Issue number2
DOIs
StatePublished - Jan 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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