ROLES FOR THE HELIODYNAMIC HORMONES, ALL-TRANS-RETINOIC ACID AND 1-ALPHA,25-DIHYDROXYVITAMIN-D3, IN CONTROL OF THE HEMATOPOIETIC-CELL CYCLE

It is now well established that the production of primary hematopoietic cells is controlled at different levels of the biological organization. Bone marrow (BM) stromal cells, the extracellular matrix (ECM), polypeptide hematopoietic growth factors (HGF) as well as endogenous cell-division cycle (CDC) related factors play a dominant role in this control. Recent information suggest that the 2 lipophilic hormones, transRA and 1-alpha,25D3, depending on and/or perhaps mediating solar energy, play a role in the maintenance of BM homeostasis. Here we show that both transRA and 1-alpha,25D3: a) modulate the growth and/or stimulate the adipocytic differentiation of fibroblastic stromal cells (F-CFU); b) inhibit the synthesis and extracellular processing but stimulate the solubilization of matrix collagen; c) modulate the clonal growth of myeloid progenitor cells (GM-CFU) in synergy with HGFs; and d) inhibit the production of lactic acid in standard, normal long-term BM cultures (LTBMC). Comparative analysis of normal, preleukemic and leukemic BM cells in LTBMC indicated a positive correlation between the induction of terminal differentiation and reduced lactate production elicited by transRA or 1-alpha,25D3. These results raise a hypothesis according to which the terminal differentiation induced by the heliodynamic hormones is dependent on the mitochondrial aerobic ATP-generating system whose impairment may be a critical step during the process of leukemic transformation.