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J. Biol. Chem., Vol. 277, Issue 16, 13463-13472, April 19, 2002

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Activation of Clg, a Novel Dbl Family Guanine Nucleotide Exchange Factor Gene, by Proviral Insertion at Evi24, a Common Integration Site in B Cell and Myeloid Leukemias^*

Karen L. Himmel^§, Feng Bi^¶, Haifa Shen, Nancy A. Jenkins, Neal G. Copeland, Yi Zheng^¶, and David A. Largaespada^**

From the  University of Minnesota Cancer Center, Institute of Human Genetics, and the Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, the ^¶ Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and the  Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Retroviruses induce leukemia in inbred strains of mice by activating cellular proto-oncogenes and/or inactivating tumor suppressors. The proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. Here we show that Evi24, a common site of retroviral integration in AKXD B cell and BXH-2 myeloid leukemias, contains a novel Dbl family guanine nucleotide exchange factor gene. We have designated this gene Clg (common-site lymphoma/leukemia guanine nucleotide exchange factor). Proviral integrations on chromosome 7 at Evi24 are located 7.6-10.3 kb upstream of Clg and increased Clg expression 2-5-fold compared with leukemias lacking proviral integrations at Evi24. Clg contains Dbl/pleckstrin homology domains with substantial sequence homology to many Rho family activators, including the transforming Dbl and Dbs/Ost oncogenes. Nucleotide exchange assays indicated that Clg specifically activated nucleotide exchange on Cdc42, but not RhoA or Rac1, in vitro. NIH 3T3 transfection studies showed that overexpression of full-length and carboxyl-terminally truncated forms of Clg morphologically transformed NIH 3T3 cells. This study and studies showing that the human homolog of EVI24 is located in a region of 19q13 frequently amplified in B cell lymphomas and pancreatic and breast cancers implicate Clg and Cdc42 activation in mouse and human cancers.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF465238.

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