Bruno Calabretta, MD, PhD

Molecular mechanisms of normal hematopoiesis and BCR/ABL-dependent leukemogenesis. The process of normal hematopoiesis requires the sequential coordination of many complex events. These include the interaction of stimulatory growth factors with their membrane receptors, generation of the appropriate signal followed by its transduction through the cell membrane and cytoplasm into the nucleus, and finally, DNA synthesis and cell division. Accordingly, it seems reasonable to assume that perturbations in any of these controlled events are likely to result in altered cell growth patterns and possibly in the emergence of cells with a leukemic phenotype, especially in the presence of cumulative alterations in these various components of the proliferative program. As a paradigm of this concept, our studies center on the investigation of the role of the oncogenic BCR/ABL protein in transformation of hematopoietic stem cells and in the role of transcription factors with hematopoietic-specific functions (c-Myb and C/EBPalpha) in normal hematopoiesis and in leukemogenesis.In particular, the studies in the BCR/ABL area will focus on the mechanisms involved in suppression of apoptosis and autophagy. The studies on c-Myb and C/EBPalpha will focus on the effects of these two transcription factors on regulation of normal and leukemic stem cells.