SHP2 is required for BCR-ABL1-induced hematologic neoplasia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Tyrosine kinase inhibitors (TKIs) transformed Philadelphia chromosome-positive (Ph+) hematologic neoplasm treatment.
• Acquired TKI resistance and limited efficacy in Ph+ B-cell acute lymphoblastic leukemia (B-ALL) remain challenges.
• GAB2 adaptor protein, essential for BCR-ABL1 leukemogenesis, activates SHP2 phosphatase.

Purpose of the Study:

• Investigate the role of SHP2 in BCR-ABL1-evoked myeloid and lymphoid neoplasia.
• Determine the specific domains and activities of SHP2 required for BCR-ABL1+ cell proliferation.
• Elucidate the downstream signaling pathways regulated by SHP2 in BCR-ABL1 transformation.

Main Methods:

• Genetic loss-of-function approach using Ptpn11 deletion.
• In vivo bone marrow transplantation models for chronic myeloid leukemia (CML) and BCR-ABL1+ B-ALL.
• Analysis of pre-B-cell proliferation, signaling pathways (MEK/ERK, SFK), and transcriptional programs (RNAseq).

Main Results:

• SHP2 is essential for BCR-ABL1-evoked myeloid and lymphoid leukemogenesis, impairing CML and B-ALL.
• SHP2's SH2 domains, PTP activity, and C-terminal tyrosines are critical for BCR-ABL1+ pre-B-cell proliferation.
• SHP2 regulates MEK/ERK and SFK activation specifically in BCR-ABL1+ cells, distinct from WT cells.
• Distinct SHP2-dependent transcriptional programs identified in BCR-ABL1+ versus WT pre-B cells.

Conclusions:

• SHP2 is a critical mediator of BCR-ABL1 leukemogenesis.
• SHP2 signaling, involving SFKs and ERK, represses MXD3/4 to promote MYC-driven proliferation in BCR-ABL1+ cells.
• Targeting SHP2 may offer a therapeutic strategy for TKI-resistant Ph+ leukemias.