Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
Fitzpatrick, Ethan R
Whitehead, Ian P
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CitationTala, Ilona, Ru Chen, Tinghui Hu, Ethan R Fitzpatrick, David A Williams, and Ian P Whitehead. 2014. “Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression.” Leukemia 27 (5): 1080-1089. doi:10.1038/leu.2012.351. http://dx.doi.org/10.1038/leu.2012.351.
AbstractWe have previously identified a tyrosine kinase-independent, guanine nucleotide exchange factor (GEF) activity that is contained within the region of p210 BCR/ABL that distinguishes it from p190 BCR/ABL. In the current study we have compared the transforming activity of p190 BCR/ABL, p210 BCR/ABL, and a mutant that lacks GEF activity (p210 BCR/ABL(S509A)). In cell-based, ex vivo, and murine bone marrow transplantation assays (BMT) the transforming activity of p210 BCR/ABL(S509A) mimics p190 BCR/ABL, and is distinct from p210 BCR/ABL. Thus, in the BMT assay, the p190 BCR/ABL and p210 BCR/ABL(S509A) transplanted mice exhibit a more rapid onset of disease than mice transplanted with p210 BCR/ABL. The reduced disease latency is associated with erythroid hyperplasia in the absence of anemia, and expansion of the MEP, CMP and GMP populations, producing a phenotype that is similar to acute myeloid leukemia (AML-M6). The disease phenotype is readily transplantable into secondary recipients. This is consistent with ex vivo clonogenicity assays where p210 BCR/ABL preferentially supports the growth of CFU-GM, while p190 BCR/ABL and the mutant preferentially support the growth of BFU-E. These results suggest that the GEF activity that distinguishes p210 BCR/ABL from p190 BCR/ABL actively regulates disease progression.
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