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Chronic Myeloproliferative Neoplasias

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

Leukemia volume 27, pages 1080–1089 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by Public Health Service grants CA097066 (IPW) and DK62757 (DAW). NIH grants CA097066 (IPW) and DK62757 (DAW).

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Authors and Affiliations

  1. New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    I Tala, R Chen, T Hu, E R Fitzpatrick & I P Whitehead

  2. Hematology/Oncology Division, Children’s Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    D A Williams

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Tala, I., Chen, R., Hu, T. et al. Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression. Leukemia 27, 1080–1089 (2013). https://doi.org/10.1038/leu.2012.351

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