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Blood, 15 January 2005, Vol. 105, No. 2, pp. 784-793.
Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-04-1508.
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NEOPLASIA
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, and
Takuro Nakamura
From the Department of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; the Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD; the Institute of Molecular and Cell Biology and Oncology Research Institute, Singapore, Singapore; and the Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
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-HOXA9 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.
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