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

I. Tala, R. Chen, T. Hu, E. R. Fitzpatrick, D. A. Williams, I. P. Whitehead

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1080-1089
Number of pages10
JournalLeukemia
Volume27
Issue number5
DOIs
StatePublished - May 2013

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Keywords

  • Rho GTPase
  • RhoGEF domain
  • chronic myelogenous leukemia
  • p210 BCR/ABL

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