On the role of the retinoblastoma tumor suppressor gene in hematopoietic differentiation

Detta är en avhandling från Gösta Bergh, Kävlingev 1, S-222 40 Lund, Sweden

Sammanfattning: The aim of this study was to investigate the role of some tumor suppressor gene products (with emphasis on the retinoblastoma suppressor gene product) in the regulation of differentiation and proliferation in leukemic and normal hematopoietic cells. For this purpose, the expression of the tumor suppressor genes RB, p53 and p16 were artificially altered. Cells used were human leukemic cell lines and isolated human bone marrow progenitors. The results show that the retinoblastoma protein, pRb, is involved in the differentiation of human leukemic cell lines, probably through mechanisms that are separate from pRb’s well established ability to regulate cell cycle progression. Suppression of pRb by antisense RB oligonucleotides in isolated bone marrow cells inhibited the monocytic maturation but simultaneously promoted the alternative neutrophilic pathway, indicating an important role for pRb in human myeloid lineage commitment. Again, this effect of pRb seemed mediated through mechanisms distinct from pRb’s cell cycle regulatory potential. Artificial over expression of p53 in leukemic cells lacking p53 made them more responsive to differentiation signals. Arrest of cell proliferation did not enhance the capacity for differentiation, suggesting that cell differentiation and cell cycle regulation are separately regulated processes.

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