Distinct Gab2-Mediated Signaling Pathways Are Essential for Myeloid or Lymphoid Transformation and Leukemogenesis by BCR-ABL

Abstract The BCR-ABL oncogene encodes an activated fusion tyrosine kinase that causes chronic myelogenous leukemia (CML) and B-lymphoid acute lymphoblastic leukemia (B-ALL) in humans. An autophosphorylation site at Tyr 177 of BCR-ABL recruits Grb2 via its SH2 domain, and is required for efficient induction of CML-like myeloproliferative disease by BCR-ABL in a mouse BM retroviral transduction/transplantation model. We showed previously (Sattler et al., Cancer Cell2002;1:479) that the scaffolding/adapter protein Gab2 is recruited to Y177 of BCR-ABL via a Grb2/Gab2 complex, and in vitro transformation of primary myeloid and lymphoid progenitors by BCR-ABL was impaired in bone marrow from mice with homozygous null mutations in the Gab2 gene (Gab2−/− mice), coincident with decreased activation of the ERK and Akt signaling pathways. Here, we demonstrate an essential requirement for Gab2 in myeloid and lymphoid leukemogenesis by BCRABL. Whereas recipients of BCR-ABL-transduced Gab2+/+ BM develop fatal CML-like myeloproliferative disease within 4 weeks of transplantation, recipients of BCR-ABLtransduced Gab2−/− BM fail to develop CML but succumb after a long latent period to T-cell acute lymphoblastic leukemia, phenocopying the disease induced by the BCR-ABL Y177F mutant. These results suggest that the Y177F and Gab2 mutations have an epistatic relationship, and that the critical transforming signals from Tyr177 of BCR-ABL are transmitted through Gab2. Co-expression of Gab2 with BCR-ABL in Gab2−/− BM restored efficient induction of CML-like leukemia, but mutants of Gab2 that lacked either the pleckstrin homology domain or Tyr binding sites for the SH2 domains of the downstream Gab2 effector molecules SHP2 or p85 PI3K failed to rescue myeloid leukemogenesis by BCR-ABL, although the mutant Gab2 proteins were expressed in circulating myeloid cells. Gab2 deficiency attenuated B-lymphoid transformation by BCR-ABL in vitro, and significantly prolonged the latency of B-ALL induced by BCR-ABL in mice. In contrast to CML, induction of B-ALL in Gab2−/− BM was rescued by either WT Gab2 or the Gab2 mutant defective in p85 binding. These results demonstrate that BCR-ABL absolutely requires signaling via Gab2 to both SHP2 and PI3K to cause CML, while a Gab2-SHP2 signaling pathway contributes to the pathogenesis of BCR-ABL+ B-ALL.

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