| Chromosomal translocations that fuse the Mixed Lineage Leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. The wild-type MLL protein is a functional homolog of the Drosophila Trithorax, and is required for the maintenance but not initiation of Hox gene expression. However, the mechanism by which MLL maintains target gene expression remains unclear. We discovered that MLL directly binds to CBP, a well-know transcriptional coactivator and histone acetyltransferase. Furthermore, recruitment of CBP is required for MLL-mediated transcriptional activation. Together, these data suggests that CBP may be a critical component of the MLL transcriptional complex and contributes to the epigenetic regulation of MLL target genes.; Our finding that wild-type MLL recruits CBP for transcriptional activation suggests a potential mechanism by which the t(11;16) encoded MLL-CBP fusion protein contributes to leukemogenesis. We hypothesize that the permanent fusion of MLL to CBP may result in a dominant gain of MLL functions through the constitutive recruitment of CBP to MLL target sites. Consequently, the inappropriate expression of select MLL targets such as the Hox genes may contribute to malignant transformation. To test this hypothesis, we generated a conditional knock-in model to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. Consistent with our hypothesis that fusion of MLL to CBP would result in a gain-of-function mutation, MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea, MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL-fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations. |
