Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression

• Published in: Leukemia Vol. 27; no. 5; pp. 1080 - 1089
• Main Authors: Tala, I, Chen, R, Hu, T, Fitzpatrick, E R, Williams, D A, Whitehead, I P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2013; Nature Publishing Group
• Subjects: 631/80/86/2341; 692/420/755; 692/699/67/1990/283/1896; Abl gene; Acute myeloid leukemia; Anemia; Animals; Assaying; BCR gene; BCR protein; Bone marrow; Bone Marrow Transplantation; Cancer; Cancer Research; Cells, Cultured; Chromosomes; Comparative analysis; Critical Care Medicine; Development and progression; Disease Progression; Erythrocytes; Fusion Proteins, bcr-abl - physiology; Gene mutations; Genetic aspects; Genotype & phenotype; Granulocytes; Guanine; Guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - physiology; Health aspects; Hematology; Humans; Hyperplasia; Intensive; Interleukin-3 - pharmacology; Internal Medicine; Kinases; Latency; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - etiology; Leukocytes (granulocytic); Macrophages; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mutants; Nucleotides; Oncology; original-article; Phenotypes; Protein-tyrosine kinase; Proteins; Rho Guanine Nucleotide Exchange Factors; rhoA GTP-Binding Protein - physiology; Signal Transduction; Stem cell transplantation; Translocation (Genetics); Transplantation; Tyrosine; United States; United States > US; New Jersey; p210 BCR/ABL; chronic myelogenous leukemia; Rho GTPase; RhoGEF domain
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.351

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.