We have recently isolated the human homologue of the Drosophila l(3)mbt gene by exon trapping, based on its location on the long arm of chromosome 20 (20q) within a region frequently deleted in hematologic malignancies (most commonly polycythemia vera, MDS, and AML).
The l(3)mbt gene encodes a member of the polycomb group (PcG) of transcriptional regulatory proteins, which play a vital role in maintaining the proper expression of key genes, such as homeobox-containing and cell cycle regulatory genes. Evidence linking abnormalities in the expression or function of PcG genes with the development or progression of several types of human cancer is now emerging (e.g., lymphoma, Hodgkin's disease, and multiple myeloma).
The human l(3)mbt protein is highly homologous to the lethal malignant brain tumor [l(3)mbt] protein, which functions as a tumor suppressor gene in Drosophila. To more completely define the role of the human l(3)mbt gene in hematologic cancers, we are assessing its genomic integrity and the relative levels of l(3)mbt expression in primary, human myeloid malignancy samples. We are defining the biological effects of l(3)mbt by expressing wild type and mutant forms in hematopoietic cells and by identifying true l(3)mbt target genes in myeloid cells.
We are also characterizing l(3)mbt-interacting proteins and the multi-protein complex that contains the l(3)mbt protein; and we are generating l(3)mbt conditioned knock-out mice to analyze its phenotype. These studies will define whether l(3)mbt functions as a classic tumor suppressor gene or can be implicated in human cancer by haploinsufficiency.
