Genetic control of normal and aberrant hematopoiesis
- Genetic control of normal and malignant hematopoiesis
- Aberrant chromatin modification by MLL fusion proteins and their role in leukemogenesis
- Biological function of HOX homeobox genes during differentiation and maturation of hematopoietic cells
One of our research projects tries to understand the role of MLL fusion proteins as oncogenes that drive leukemogenesis. MLL fusions are the consequence of chromosomal aberrations that juxtapose the N-terminus of the histone-methyltransferase MLL (mixed lineage leukemia) with a variety of different, unrelated fusion partners. This replaces the normal histone methyltransferase activity of MLL with the biological function of the respective fusion partner. MLL fusions can be found in highly aggressive leukemia in particular in pediatric acute lymphatic leukemia. Our research demonstrated that many MLL fusion proteins act as transcriptional activators that employ a special “post-initiation” mechanism to increase transcriptional output. Several MLL fusion partners are members of a novel complex. This complex which we named EAP (ENL associated proteins, also termed AEP or SEC by other groups) contains the histone H3 methyltransferase DOT1L that deposits a methyl group on lysine 79 of the histone protein. In addition EAP also includes the RNA polymerase II C-terminal-domain kinase CDK9 and its cognate cyclinT. This cyclin/CDK dimer is known as positive transcription factor b (pTEFb). pTEFb promotes transcription by stimulating the elongation phase of RNA polymerase. The continuous recruitment of DOT1L/pTEFb activity by MLL fusion proteins leads to a block in hematopoietic differentiation because several genes normally under control of MLL cannot be switched off any more. These genes, most importantly HOX homeobox genes and their dimerization partner MEIS1 are normally downregulated during hematopoietic maturation. Their mode of action is the focus of our second project.
HOX homeobox genes are potent oncogenes in the hematopoietic system. Next to leukemia with MLL fusion involvement, HOX genes and the gene for the HOX-dimerization partner MEIS1 are also overexpressed in a variety of other acute leukemia with different etiology. Overexpression of HOX proteins, mainly from the “A” paralog group blocks hematopoietic differentiation and leads to an accumulation of rapidly self-renewing precursor cells. We are interested how HOX proteins induce cellular transformation. Because most HOX proteins are transcription factors the emphasis of our work focuses on the transcriptional programs governed by these proteins. In this respect we could already show that the known oncogene c-MYB is under control of several HOX-A proteins. Another spotlight of our research investigates how other members of the HOX-A cluster contribute to the leukemic phenotype and how specificity is achieved.
For an up to date publication list please search „PubMed“ with following URL: http://www.ncbi.nlm.nih.gov/pubmed/?term=slany+r