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Start of funding 01.01.2006
Development and functional testing of new molecules with therapeutic potential for leukemias and lymphomas
PD Dr. Robert Slany
Friedrich-Alexander-University of Erlangen-Nuremberg
Prof. Dr. B. Matija Peterlin
University of California, San Francisco
Leukemogenic oncogenes frequently block hematopoietic differentiation. This causes the immortalization and expansion of a rapidly proliferating precursor cell pool that can be the target for cooperating mutations to elicit acute leukemias. Since mature cells stop dividing the induction of differentiation has been proposed as an innovative way of treating leukemias. MLL fusion proteins derived from chromosomal translocations are a paradigm for a “differentiation-blocking” oncoprotein. MLL fusions are transcription factors that transform through ectopic activation of target genes. Evidence has been accumulating that this transcriptional activation is due to a positive effect on elongation. In this project specific inhibitors of elongation will be tested for their capacity to inhibit MLL fusion function and to induce differentiation of MLL transformed cells.
Final report:
Transcriptional elongation is an important checkpoint that determines expression of genes particularly involved in control of proliferation, differentiation and immediate response reactions. The purpose of this proposal was to unite the skills of the laboratory in Erlangen (R. Slany) that studies transcriptional elongation and its role in a special subtype of aggressive leukemia with the extensive knowledge present at UCSF (M. Peterlin) with respect to elongation control in the context of HIV biology. The medium term goal was to probe inhibitory substances and dominant negative versions of proteins involved in elongation control for their effect on leukemia development. In addition the exact role of elongation associated protein complexes during leukemogenesis should be further explored.
The grant was used to cover the costs of three mutual visits and partially to pay for the short term stay of an Erlangen student in the laboratory of M. Peterlin to learn techniques for measuring transcriptional elongation. These techniques were applied and helped to elucidate the involvement of a novel transcriptional elongation complex in the etiology of mixed lineage leukemia.
Publication:
Müller D., Bach C., Zeisig D., Garcia-Cuellar M.P., Monroe S., Sreekumar A., Zhou R., Nesvizhskii A., Chinnaiyan A., Hess J.L., and Slany R.K. (2007) A Role for the MLL Fusion Partner ENL in Transcriptional Elongation and Chromatin Modification, Blood, 110: 4445-4454.