Exploring the Negative Growth Signaling Networks in Lineage-Specific Hematopoietic Cell Differentiation and Its Implication in Leukemogenesis (I)

Leukemia is one of the major cause of cancer death in Taiwanese population. The development of leukemia usually associates with activation of oncogenes and inactivation of tumor suppressor genes leading to abrogation of normal differentiation program (i.e., hematopoiesis) that gives rise to different lineages of mature and functional blood cells. Thereby, understanding the mechanisms involved in lineage-specific hematopoietic cell differentiation not only offers a great insight of how blood cell maintains its homeostasis, but also creates an opportunity to develop therapeutic strategy to correct signaling defects within the leukemic cells. In this study, we will explore and characterize the negative growth signaling networks that play a role during hematopoietic cell differentiation. We will focus on the signaling mediated by a negative regulator Disabeld-2 (DAB2), a tumor suppressor that has been shown in a number of solid tumors and leukemia. A genetically modified mouse embryonic stem cells for inducing hematopoietic cell differentiation and a lentivirus gene transfer system for modulating the level of DAB2 with siRNA will be established. The effect of DAB2-modulating signals on lineage-specific hematopoietic cell differentiation will be determined. With this system, the change of protein profiles between the control and DAB2-modulating ES cells in both differentiated and undifferentiated stages will be determined by proteomic techniques. The potential DAB2 downstream effectors will be identified and will be further characterized for their function and regulation using molecular and cellular approaches. The ultimate goal of this study is to enforce appropriate differentiation program and tumor suppressive activity to take place in the leukemic cells that would improve the therapeutic index of leukemia.

Project ID:PC9308-2404
External Project ID:NSC93-2745-B182-006-URD