| From promoting proliferation and differentiation to maintaining homeostasis, cytokines and growth factor receptor signaling is indispensable for hematopoiesis. In the process of a hematopoietic stem cell becoming a mature blood cell, cytokines and growth factors are key players as evidenced by developmental problems associated with loss-of-function mutations in receptor genes. This thesis addresses two specific issues involving cytokine and growth factor receptors: the role of cytokine receptors in lineage commitment and the effects of constitutive signaling in hematopoietic disease.; IL-7R signaling is necessary for lymphoid development, with the expression of IL-7R being restricted to lymphoid lineage cells. Mice deficient in IL-7R exhibit a severe reduction of both B and T cells. In this thesis, the question of whether IL-7R is involved in commitment to the lymphoid lineage is addressed with an in vivo model. The unique system used to test this hypothesis involved two spectrally distinct GFP proteins which were coexpressed with the two chains of the IL-7R, IL-7Ralpha and IL-2Rgamma. While commitment to the lymphoid lineage, at the expense of myeloid commitment, was not observed, a block in B cell development at a very early stage did occur. Enforced expression of IL-7R on hematopoietic progenitor cells suggests a possible role in commitment within, but not to, the lymphoid lineage and downregulation of IL-7R seems to be necessary for B cell development.; FLT3 mutations, resulting in constitutive activation of the receptor, are the most common genetic aberrations found in acute myeloid leukemia (AML). While a FLT3 mutation by itself does not result in leukemia, in combination with other mutations, such as chromosomal translocations, leukemic progression may occur. This hypothesis was tested by a bone marrow transplantation model where the AML1-ETO protein, a common translocation found in AML was coexpressed with FLT3-ITD, which is a ligand-independent, constitutively active receptor. These mice exhibited a block in early myeloid development and a partial block in hematopoietic stem cell differentiation but did not develop leukemia. This implies that the cooperation of AML1-ETO and FLT3-ITD is not sufficient to generate AML without additional mutations. |
