This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Podocalyxin (PODXL) is a highly glycosylated and sialylated transmembrane protein, and CD34 orthologue normally expressed on hematopoietic stem cells (HSC), hemangioblasts, vascular endothelial cells, podocytes and a subset of neural progenitors. Recently, increased PODXL expression has been associated with a sub set of aggressive cancers including acute myeloid and lymphoid leukemia, myeloid sarcomas, and certain breast, liver, pancreatic and kidney tumors. Further, PODXL's overexpression is detected frequently in AML with almost all FAB subtypes. In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) induces a differentiation syndrome (DS) characterized by massive pulmonary infiltration of differentiating leukemic cells. Recently, cell surface / adhesion molecules and chemokines have been shown to play a role in DS and are speculated to facilitate migration and extravasation of differentiating leukemic cells. Interestingly, PODXL has been predicted to be involved in chemotactic signaling via CXCR4 association. Furthermore, ATRA induces PODXL expression in AML2/OCL cells. To date, however, no attempts have been made to apply an AML mouse model to critically assess the role of PODXL in leukemogenesis. Therefore, the proposed set of investigations will define PODXL's role in leukemia and will provide mechanistic insight into PODXL's role in leukemogenesis and ATRA induced differentiation syndrome in APL.
SPECIFIC AIMS : 1. Define the course of increased PODXL expression during PML/RAR-alpha induced AML 2. Employ a conditional knock-out mouse model to assess PODXL's role in the onset, and progression of PML/RAR-alpha induced AML 3. Investigate the role of PODXL in all-trans retinoic acid (ATRA) induced DS.
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