When:
Thursday, March 17, 2016
9:00 AM - 10:00 AM CT
Where: Robert H Lurie Medical Research Center, Searle Seminar Room, 303 E. Superior, Chicago, IL 60611 map it
Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students
Contact:
Carson Nestler
Group: Biochemistry & Molecular Genetics Seminar Series
Category: Lectures & Meetings
The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:
Nancy Zeleznik-Le, PhD
Professor, Department of Medicine
Cardinal Bernardin Cancer Center
Loyola University Chicago, Health Sciences Division
The Mixed Lineage Leukemia (MLL) gene at the 11q23 locus was first identified by its involvement in chromosome translocations associated with acute leukemia. MLL leukemia accounts for around 10% of AML and ALL in general, but is over-represented in two populations of patients. Up to 80% of infants with acute leukemia have MLL translocations. Additionally, a significant percentage of patients previously treated for another cancer with DNA topoisomerase II-targeting drugs develop MLL leukemia as a result of that therapy. Chromosomal translocations involving the MLL gene produce in-frame fusion oncoproteins in which the N- terminal portion of the MLL protein is fused to the C-terminal portion of one of many protein partners. Regardless of the particular MLL fusion, MLL leukemia is associated with early relapse, and patients are generally classified as poor-risk. The most common MLL fusion partners normally function as part of transcription elongation complexes which also contain PTEFb and the histone 3 lysine 79 methyltransferase DOT1L. DOT1L has three binding sites in AF9 (and its homolog ENL), common MLL partner proteins. Structure-informed mutations demonstrate that the degree of DOT1L recruitment to MLL-AF9 is linked to transformation capability, and suggest blocking this interaction as a therapeutic target. MLL normally functions to maintain expression of many developmentally important target genes. The MLL CXXC domain, which binds to nonmethylated CpG DNA, is retained in MLL fusion proteins and is essential for leukemogenic transformation. Point mutations that specifically disrupt the CXXC DNA binding ability of MLL fusions cause decreased expression of critical downstream target genes and abrogate leukemogenic capacity, thus establishing this activity as a potential target for therapeutic intervention.