Core C The cell culture will provide cell culture support for this Program Project. The assays we use can detect hematopoietic progenitors at various stages of differentiation and can distinguish between normal and leukemic colony-forming cells. These assays are well suited to address a major issue arising in this Program Project, namely the derivation ofthe cells responding to various anti-leukemic agents investigated in this P01. These assays will be used to investigate the role of extrinsic cytokines including granulocytemacrophage colony stimulating factor (GM-CSF) and c-Kit ligand in protecting CML progenitors from Imatinib (IM;Gleevec)-induces apoptosis using blood and marrow cells of both patients sensitive and resistant to Gleevec. These studies will be conducted in collaboration with Projects 4 and 5. Also, we will provide support to Project 5 in studying the effects of lipocalin and antisense 24p3 and BCR on Ph+ cell lines and on normal and brc-abl+ eariy and mature progenitors. In collaboration with Project 3 we will study whether disruption ofthe microenvironment-dedicated protection of CML progenitors will affect the sensitivity of CML colony-forming cells to protein kinase inhibitors and whether Bcl-2 inhibitors will potentiate the effects of protein kinase inhibitors. Thus, the Specific Aims are the following: 1) To investigate whether extrinsic stimulatory cytokines protect CML progenitors from apoptotic effect of IM and other protein kinase inhibitors in collaboration with Drs. Deininger (Project 4) and Arlinghaus (Project 5) 2) To study the effects of anti-24p3 and anti-NGAL antibodies and BCR (transduced by the lentivirus vector infection system) on CML cell lines and fresh CML and normal marrow cells in collaboration with Dr. Arlinghaus (Project 5). 3) To investigate how interruption ofthe interaction between the hematopoietic stroma and the CML clone would affect the sensitivity of normal and BCR-ABL+ progenitors to protein tyrosine kinase inhibitors. We will study the effect of agents that interrupt the interaction between SDF-1 and CXCR4, and the combination of tyrosine kinases and Bcl-2 inhibitors using a combination of hematopoietic stroma cultures, the long-term culture initiating cell (LTCIC) assay and donogenic assays, in collaboration with Dr. Andreeff (Project 3).
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