title: Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression.
abstract: We have previously identified a tyrosine kinase-independent, guanine nucleotide exchange factor (GEF) activity, which is contained within the region of p210 no expansion 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 (BMT) assays 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 megakaryocyte-erythrocyte progenitor (MEP), common myeloid progenitor (CMP) and granulocyte-macrophage progenitor (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 colony forming unit (CFU)-granulocyte-macrophage (GM), whereas p190 BCR/ABL and the mutant preferentially support the growth of burst forming unit-erythroid (BFU-E). These results suggest that the GEF activity that distinguishes p210 BCR/ABL from p190 BCR/ABL actively regulates disease progression.
authors.affiliation: New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.
authors.forename: I
authors.initials: I
authors.lastname: Tala
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Hu
authors.forename: E R
authors.initials: ER
authors.lastname: Fitzpatrick
authors.forename: D A
authors.initials: DA
authors.lastname: Williams
authors.forename: I P
authors.initials: IP
authors.lastname: Whitehead
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007377:Interleukin-3; D064067:Rho Guanine Nucleotide Exchange Factors; D016044:Fusion Proteins, bcr-abl; D020742:rhoA GTP-Binding Protein