Inhibition of human hematopoietic tumor formation by targeting a repressor Myb-KRAB to DNA

Abstract

In many hematopoietic malignancies, c-Myb, a nuclear transcription factor of hematopoietic cells, is an activated oncogene. To achieve a specific inhibition of hematopoietic tumor growth, an inducible fusion protein consisting of the Myb DNA binding domain (DBD) and the active repressor domain KRAB, the Krüppel-associated box of the developmental zinc-finger protein KOX-1, was generated. The MybDBD-KRAB fusion protein is a potent repressor of Myb-induced gene expression from Myb-responsive reporter genes containing several Myb binding sites. MybDBD-KRAB expressed in the human hematopoietic promyelocytic cell line HL60 significantly reduces cell proliferation by inducing apoptosis. Expression of MybDBD-KRAB in subcutaneously injected HL60 cells leads to inhibition of tumor formation in nude mice. The MybDBD-KRAB effect is specific to cell lines expressing c-Myb. It is conceivable to fuse the KRAB domain to other DBDs of oncogenic transcription factors and target them to their respective DNA response elements to selectively drive tumor cells into apoptosis.