The GAB2/SHP2 Pathway in BCR-ABL1-Induced Hematopoietic Neoplasia

BCR-ABL1 is a gene product of the t(9, 22) chromosomal translocation. It encodes a fusion protein with constitutively activated tyrosine kinase activity and is the direct cause of chronic myeloid leukemia (CML) and a subset of B-lymphoid acute lymphoblastic leukemia (B-ALL). ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of BCR- ABL1+ hematopoietic neoplasia, but CML patients suffer from persistence of leukemic stem cells (LSCs), and B-ALL patients exhibit poorer response at diagnosis compared with CML patients. Over time, such patients succumb to TKI-resistant leukemic clones. Therefore, additional therapeutic targets are needed to cure these malignancies. I assessed the role of the protein-tyrosine phosphatase (PTP) SHP2 in the initiation and/or maintenance of CML and BCR- ABL1+ B-ALL. I found that SHP2 is required for initiation and maintenance of CML, consistent with its essentiality in normal hematopoietic stem cells (HSCs). In BCR-ABL1+ B-ALL, SHP2 is specifically required for the proliferation of BCR-ABL1+, but not WT, B lymphoid progenitors. The SFK and MEK-ERK pathways downstream of SHP2 independently contribute to this differential requirement. I also assessed the role of GAB2 in downstream signaling from BCR- ABL1, and found that its interaction with SHP2 or PI3K activates different signaling pathways, potentially underlying the differential requirement of these interactions for BCR-ABL1-evoked myeloid and lymphoid malignancies. Furthermore, in a parallel set of studies, I developed a mathematical model to simulate the clinical course of high-grade serous ovarian carcinoma, with potential implications for treatment and screening of this disease. This work is described in the Appendix.Ph.D