Hematopoiesis describes the formation and development of blood cells. All blood cells originate from a pluripotent hematopoietic stem cell (HSC) which has the capacity for long and short term self-renewal as well as differentiation into myeloid or lymphoid lineages. The balance between HSC differentiation and proliferation is tightly controlled by both extrinsic and intrinsic factors. During leukemogenesis, this regulation is disrupted as transformation events lead to changes in proliferation, differentiation, and survival. Two distinct experimental strategies were utilized to examine the role of the hematopoietic adaptor protein GADS (GRB2-related adaptor downstream of SHC) in both leukemogenesis and in normal hematopoiesis. Philadelphia chromosome positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and B cell acute lymphoblastic leukemia (B-ALL), are mediated by the oncogenic BCR-ABL fusion protein. Animal modeling experiments utilizing retroviral transduction and subsequent bone marrow transplantation have demonstrated that BCR-ABL generates both myeloid and lymphoid disease in mice when whole bone marrow is used as donor material. Strikingly, we observe that the lymphoid disease is absent in experiments completed with Gads-deficient bone marrow expressing BCR-ABL. Gads-deficient mice were generated previously and display a decrease in mature T cells, indicating that GADS is critical to T cell differentiation. Through immunophenotyping analysis we observed that Gads-deficient mice have increased numbers of lymphoid progenitors and HSCs. The increased number of HSCs in Gads-deficient mice did not induce enhanced HSC function as Gads-deficient bone marrow cells have impaired repopulation potential. Our data suggests that the T cell defect previously observed in Gads-deficient mice may be due to an early block in differentiation and functional defect in the HSC. Taken together, our studies demonstrate that GADS is a critical mediator in the hematopoietic system for both normal and leukemic differentiation and proliferation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/35716 |
| Date | 18 July 2013 |
| Creators | Gillis, Lisa |
| Contributors | Barber, Dwayne |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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