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Molecular and Cellular Biology, March 2000, p. 1970-1981, Vol. 20, No. 6
0270-7306/00/$04.00+0

Regulation of the Resident Chromosomal Copy of c-myc by c-Myb Is Involved in Myeloid Leukemogenesis

M. Schmidt,1 V. Nazarov,1,dagger L. Stevens,2 R. Watson,3 and L. Wolff1,*

Laboratory of Cellular Oncology1 and Laboratory of Genetics,2 National Cancer Institute, Bethesda, Maryland, and Ludwig Institute for Cancer Research, Imperial College School of Medicine at St. Mary's, London, United Kingdom3

Received 13 October 1999/Returned for modification 12 November 1999/Accepted 16 December 1999

c-myb is a frequent target of retroviral insertional mutagenesis in murine leukemia virus-induced myeloid leukemia. Induction of the leukemogenic phenotype is generally associated with inappropriate expression of this transcriptional regulator. Despite intensive investigations, the target genes of c-myb that are specifically involved in development of these myeloid lineage neoplasms are still unknown. In vitro assays have indicated that c-myc may be a target gene of c-Myb; however, regulation of the resident chromosomal gene has not yet been demonstrated. To address this question further, we analyzed the expression of c-myc in a myeloblastic cell line, M1, expressing a conditionally active c-Myb-estrogen receptor fusion protein (MybER). Activation of MybER both prevented the growth arrest induced by interleukin-6 (IL-6) and rapidly restored c-myc expression in nearly terminal differentiated cells that had been exposed to IL-6 for 3 days. Restoration occurred in the presence of a protein synthesis inhibitor but not after a transcriptional block, indicating that c-myc is a direct, transcriptionally regulated target of c-Myb. c-myc is a major target that transduces Myb's proliferative signal, as shown by the ability of a c-Myc-estrogen receptor fusion protein alone to also reverse growth arrest in this system. To investigate the possibility that this regulatory connection contributes to Myb's oncogenicity, we expressed a dominant negative Myb in the myeloid leukemic cell line RI-4-11. In this cell line, c-myb is activated by insertional mutagenesis and cannot be effectively down regulated by cytokine. Myb's ability to regulate c-myc's expression was also demonstrated in these cells, showing a mechanism through which the proto-oncogene c-myb can exert its oncogenic potential in myeloid lineage hematopoietic cells.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, National Cancer Institute, Bldg. 37, Rm. 2D11, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-6763. Fax: (301) 594-3996. E-mail: lwolff{at}helix.nih.gov.

dagger Present address: Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia.

Molecular and Cellular Biology, March 2000, p. 1970-1981, Vol. 20, No. 6
0270-7306/00/$04.00+0


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