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Critical role for Gab2 in transformation by BCR/ABL
Martin Sattler1, M Golam Mohi, Yuri B Pride
1Dana-Farber Cancer Institute, Department of Adult Oncology, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.
Cancer Cell
|July 19, 2002
Summary
The scaffolding adaptor Gab2 is recruited by BCR/ABL tyrosine 177, impacting chronic myelogenous leukemia (CML) development. Gab2 is crucial for BCR/ABL-driven myeloid and lymphoid leukemogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- The BCR/ABL oncogene drives chronic myelogenous leukemia (CML) and other leukemias.
- p210 BCR/ABL is a tyrosine kinase critical for leukemogenesis.
- Tyrosine 177 (Tyr177) of BCR/ABL influences disease lineage and severity.
Purpose of the Study:
- To elucidate the signaling pathway downstream of BCR/ABL Tyr177.
- To investigate the role of Gab2 in BCR/ABL-mediated leukemogenesis.
Main Methods:
- Utilized Ba/F3 cell lines expressing wild-type BCR/ABL and BCR/ABL-Y177F mutant.
- Analyzed protein phosphorylation, complex formation, and downstream signaling pathways (PI3K/Akt, Ras/Erk).
- Employed Gab2 knockout (Gab2-/-) mouse models for myeloid and lymphoid progenitor studies.
Main Results:
- BCR/ABL Tyr177 recruits Gab2 via a Grb2/Gab2 complex.
- BCR/ABL-Y177F mutants show reduced Gab2 phosphorylation, PI3K/Akt, and Ras/Erk activation.
- Gab2 deficiency impairs BCR/ABL-induced myeloid transformation and increases lymphoid cell apoptosis.
- Gab2 is essential for BCR/ABL-driven activation of PI3K/Akt and Ras/Erk pathways in primary hematopoietic cells.
Conclusions:
- Gab2 and its associated proteins are critical mediators of BCR/ABL oncogene activity.
- Gab2 signaling dictates the lineage and severity of BCR/ABL-induced leukemia.
- Targeting the Gab2 pathway may offer therapeutic strategies for CML.