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

We 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, a...

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Autores principales: Tala, Ilona, Chen, Ru, Hu, Tinghui, Fitzpatrick, Ethan R, Williams, David A, Whitehead, Ian P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931524/
https://www.ncbi.nlm.nih.gov/pubmed/23207522
http://dx.doi.org/10.1038/leu.2012.351
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author Tala, Ilona
Chen, Ru
Hu, Tinghui
Fitzpatrick, Ethan R
Williams, David A
Whitehead, Ian P
author_facet Tala, Ilona
Chen, Ru
Hu, Tinghui
Fitzpatrick, Ethan R
Williams, David A
Whitehead, Ian P
author_sort Tala, Ilona
collection PubMed
description We 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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spelling pubmed-39315242014-02-21 Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression Tala, Ilona Chen, Ru Hu, Tinghui Fitzpatrick, Ethan R Williams, David A Whitehead, Ian P Leukemia Article We 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. 2012-12-04 2013-04 /pmc/articles/PMC3931524/ /pubmed/23207522 http://dx.doi.org/10.1038/leu.2012.351 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Tala, Ilona
Chen, Ru
Hu, Tinghui
Fitzpatrick, Ethan R
Williams, David A
Whitehead, Ian P
Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title_full Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title_fullStr Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title_full_unstemmed Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title_short Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression
title_sort contributions of the rhogef activity of p210 bcr/abl to disease progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931524/
https://www.ncbi.nlm.nih.gov/pubmed/23207522
http://dx.doi.org/10.1038/leu.2012.351
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