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The CCL6 Chemokine Is Differentially Regulated by c-Myc and L-Myc, and Promotes Tumorigenesis and Metastasis¹

Section of Hematology/Oncology, Departments of Pediatrics [F. Y., E. V. P.] and Pathology [R. J.], Children’s Hospital of Pittsburgh; The Department of Molecular Genetics and Biochemistry, The University of Pittsburgh Medical Center [E. V. P.]; and the University of Pittsburgh Cancer Institute [E. V. P.], Pittsburgh, Pennsylvania 15213

The CCL6 chemokine gene was identified as a direct positive target of the L-Myc oncoprotein in interleukin 3-dependent 32D myeloid cells. A mutant form of c-Myc, lacking a region of the NH₂-terminal domain necessary for transcriptional repression (c-MycMBII), also up-regulated CCL6. Chromatin immunoprecipitation showed that L-Myc, c-MycMBII, and full-length c-Myc all bound the CCL6 promoter, although the latter was inactive in transcriptional up-regulation. Exogenously added CCL6 induced marked apoptosis in some cell types. However, in 32D cells, the coexpression of c-Myc and CCL6 abrogated interleukin 3 dependence and produced a highly leukemogenic phenotype. In two solid tumor models, CCL6 overexpression also accelerated tumor growth, and/or enhanced local and metastatic spread in association with marked apoptosis of the tumor capsule and adjacent normal tissues. Our results show that CCL6 can be either a positive or negative target for Myc oncoproteins. The chemokine may alter tumor behavior by relieving its growth factor dependency and by promoting invasiveness as a result of local tissue apoptosis.

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