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

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.

• Authors: S Gu, A Sayad, G Chan, W Yang, Z Lu, C Virtanen, R A Van Etten, B G Neel
• Journal: Leukemia (Leukemia) Vol. 32 Issue 1 Pg. 203-213 (01 2018) ISSN: 1476-5551 [Electronic] England
• PMID: 28804122 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Protein Kinase Inhibitors
• Fusion Proteins, bcr-abl
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Apoptosis (drug effects, genetics)
• Cell Line
• Cell Proliferation (drug effects, genetics)
• Cell Transformation, Neoplastic (genetics, pathology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Fusion Proteins, bcr-abl (genetics)
• HEK293 Cells
• Hematologic Neoplasms (drug therapy, genetics, pathology)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Myeloproliferative Disorders (drug therapy, genetics, pathology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (genetics)
• Signal Transduction (drug effects, genetics)
• src Homology Domains (genetics)