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Leukemia. 2018 Jan;32(1):203-213. doi: 10.1038/leu.2017.250. Epub 2017 Aug 14.

SHP2 is required for BCR-ABL1-induced hematologic neoplasia.

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
2
Princess Margaret Cancer Center, Toronto, Ontario, Canada.
3
Department of Orthopaedics, Brown University Alpert Medical School, Providence, RI, USA.
4
Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, University of California, Irvine, Irvine, CA, USA.

Abstract

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 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, are essential for BCR-ABL1+, but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (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.

PMID:
28804122
PMCID:
PMC6005183
DOI:
10.1038/leu.2017.250
[Indexed for MEDLINE]
Free PMC Article

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