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"CONTRIBUTIONS OF THE RHOGEF ACTIVITY OF P210 BCR/ABL TO DISEASE PROGRESSION IN CHRONIC MYELOGENOUS LEUKEMIA"

by
Ilona Tala
Interdisciplinary Biomedical Sciences Program
B.S. 2006, Montclair State University


Thesis Advisor: Ian P. Whitehead, Ph.D.
Professor
Department of Microbiology and Molecular Genetics

Wednesday, April 24, 2013
12:00 P.M., Cancer Center, G-1196


Abstract

p210 BCR/ABL and p190 BCR/ABL are two fusion proteins associated with chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL), respectively. Whereas both of these fusion proteins contain equivalent ABL derived sequences, they differ in the amount of BCR sequence at the NH2-terminus. Previous studies from our lab have identified a domain with guanine nucleotide exchange factor (GEF) activity, which is contained within the BCR sequences of p210 BCR/ABL that distinguishes it from p190 BCR/ABL. In the current study we have compared the transforming activity of p210 BCR/ABL, p190 BCR/ABL and a mutant p210 BCR/ABL (p210 BCR/ABL (S509A)), which is significantly impaired in its GEF activity. When examined in cell-based, ex-vivo, and murine bone marrow transplantation (BMT) assays, the transforming activity of p210 BCR/ABL(S509A) mimics p190 BCR/ABL, and is distinct from p210 BCR/ABL. In the BMT assay, p190 BCR/ABL and p210 BCR/ABL(S509A) transplanted mice exhibit a more rapid onset of disease than mice transplanted with p210 BCR/ABL. This shortened disease latency is associated with erythroid hyperplasia in the absence of anemia, and expansion of the myelo-erythroid progenitor populations, producing a phenotype similar to acute myeloid leukemia M6 (AML-M6). The disease phenotype is readily transplantable into secondary recipients. Taken together, these results suggest that the GEF activity that distinguishes p210 BCR/ABL from p190 BCR/ABL actively regulates disease progression.


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