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Arthur Zelent, Ph.D.
Institutional Affiliation:
Reader in Biochemistry
Career Faculty
Team Leader
Institute of Cancer Research, United Kingdom
http://www.icr.ac.uk/research/research_profiles/2892.shtml
Education
Rutgers University, Rutgers College, B.A.
City University of New York,
Mount Sinai School of Medicine, Ph.D.
Research
Transcriptional Controls in Leukaemia
Impact
The goal of our research is focused on the development of better approaches to cancer treatment through elucidation of molecular mechanisms underlying transcriptional deregulation and pathogenesis of leukaemia.
Summary of Research
The importance of some transcriptional regulators in haematopoiesis is reflected by frequent abnormalities of their genes in various haematopoietic malignancies. For example, acute promyelocytic leukaemia (APL) has consistently been associated with translocations of a nuclear receptor superfamily member, the retinoic acid receptor-α (RARα) gene located on chromosome 17q21. To date, five different translocations of RARα have been described, including the t(11;17)(q23;q21), which was discovered in my laboratory. The molecular characterisation of this translocation led to the isolation of the Promyelocytic Leukaemia Zinc Finger (PLZF) gene, which encodes a histone deacetylase dependent transcriptional repressor. Studies addressing functional properties of PLZF as well as APL associated PML- and PLZF-RARα fusion oncoproteins have shown that abnormal transcriptional repression plays an important role in the molecular pathogenesis of APL. Subsequent work with other leukaemia associated fusion transcription factors, such as TEL-AML1 for example, indicated that this mechanism is more general in human leukaemia and suggested potential use of agents targeting the histone deacetylase component of the co-repressor complex in anti-leukaemic therapy. These earlier studies form a framework for our current research programme, which further addresses the molecular pathogenesis of acute leukaemia and mechanisms underlying cancer cell differentiation, with particular emphasis on the role of epigenetic factors and vitamin A signalling influencing gene expression during leukaemic cell differentiation. The long-term objective of this work is to translate our basic findings into more successful transcriptional therapies of leukaemia and cancer in general.
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