Adam N. Goldfarb, MD

Adam N. Goldfarb, MD

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Molecular determinants regulating megakaryocytic commitment in bone marrow

One of the most common complications of dose intensive chemotherapy is poor platelet recovery due to defective megakaryocyte regeneration. While effective treatments have been developed to enhance post-chemotherapy recovery of neutrophils and red cells, no effective therapies currently exist to promote platetelet recovery in patients treated with chemotherapy. The basis for the defective megakaryocytic recovery in this patient population appears to lie at an early step in megakaryocyte development, most likely the lineage commitment event. Megakaryocytes derive from bipotent bone marrow progenitor cells known as BFU-E/MK (burst forming units- erythroid/mega-karyocytic) or as MEP (megakaryocytic-erythroid progenitors), which can give rise to either megakaryocytes or red cells (erythroid lineage). The Goldfarb laboratory focuses on the molecular determinants of the divergence of the erythroid and megakaryocytic lineages.  The intent of these studies is to identify pathways, which may be manipulated to enhance megakaryocytic lineage commitment in recovering bone marrows.

This research program depends heavily on several core facilites at University of Virginia: the molecular biology core facility for sequencing and microarray analysis, the flow cytometry core facility for analysis and sorting of human hematopoietic stem cells during development, the tissue culture core facility for cell culture reagents, and the confocal microscopy core facility for high-resolution immunofluorescence/GFP analysis. Collaborators and consultants have included Dr. Isa Hussaini in the Department of Pathology at University of Virginia (copublished in 2004: Elagib et al), Dr. John Bushweller in the Department of Physiology and Biophysics at University of Virginia, and Dr. David Allis formerly of the Department of Biochemistry at University of Virginia. In earlier work, they also collaborated with Dr. Don Hunt in the Department of Chemistry at University of Virginia. The collaboration with Dr. Hunt attempted to use mass spectrometry to define erythro-megakaryocytic transcriptional complexes; the project was funded by a Cancer Center pilot grant.

A second more recent Cancer Center pilot grant has permitted them to delve into the mechanism of c-Jun mediated apoptosis in normal human erythroid progenitors. This finding arose from an initial hypothesis that c-Jun might participate in megakaryocytic divergence from the erythroid lineage. Upon testing this hypothesis by retroviral transduction of human CD34+ cells, they found that c-Jun potently induced apoptosis at an early stage of erythroid lineage commitment through a novel target-gene-independent, COP1-dependent mechanism.  They believe that this mechanism is relevant to the problems in erythroid development seen in myelodysplastic syndromes, chronic myelogenous leukemia, and iron deficiency anemia. Progress on discerning this underlying mechanism has recently been sufficient to begin writing an R01 application on this topic.