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...

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Autores principales: Gu, Shengqing, Sayad, Azin, Chan, Gordon, Yang, Wentian, Lu, Zhibin, Virtanen, Carl, Van Etten, Richard A., Neel, Benjamin G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
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.
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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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