SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph(+)) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph(+) B-cell acut...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005183/ https://www.ncbi.nlm.nih.gov/pubmed/28804122 http://dx.doi.org/10.1038/leu.2017.250 |
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author | Gu, Shengqing Sayad, Azin Chan, Gordon Yang, Wentian Lu, Zhibin Virtanen, Carl Van Etten, Richard A. Neel, Benjamin G. |
author_facet | Gu, Shengqing Sayad, Azin Chan, Gordon Yang, Wentian Lu, Zhibin Virtanen, Carl Van Etten, Richard A. Neel, Benjamin G. |
author_sort | Gu, Shengqing |
collection | PubMed |
description | BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph(+)) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1(+) B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1(+) B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1(+), but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1(+) pre-B cells, but is only required for the proliferation of BCR-ABL1(+) cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1(+) pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1(+) and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells. |
format | Online Article Text |
id | pubmed-6005183 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
record_format | MEDLINE/PubMed |
spelling | pubmed-60051832018-06-18 SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia Gu, Shengqing Sayad, Azin Chan, Gordon Yang, Wentian Lu, Zhibin Virtanen, Carl Van Etten, Richard A. Neel, Benjamin G. Leukemia Article BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph(+)) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1(+) B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1(+) B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1(+), but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1(+) pre-B cells, but is only required for the proliferation of BCR-ABL1(+) cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1(+) pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1(+) and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells. 2017-08-14 2018-01 /pmc/articles/PMC6005183/ /pubmed/28804122 http://dx.doi.org/10.1038/leu.2017.250 Text en Users may view, print, copy, and download 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 Gu, Shengqing Sayad, Azin Chan, Gordon Yang, Wentian Lu, Zhibin Virtanen, Carl Van Etten, Richard A. Neel, Benjamin G. SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title | SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title_full | SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title_fullStr | SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title_full_unstemmed | SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title_short | SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasia |
title_sort | shp2 is required for bcr-abl1-induced hematologic neoplasia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005183/ https://www.ncbi.nlm.nih.gov/pubmed/28804122 http://dx.doi.org/10.1038/leu.2017.250 |
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