Apoptotic mechanism is in unilineage hematopoietic differentiation

Hematopoiesis results from a complex network of stimulatory, inhibitory and apoptotlc signals. Bcl-2, ocArand bag- J.the major antiαpoptotic members of bcl2 family, are expressed in purified hematopoietic progenitor cells (HPCs) and upmodulated after growth factor stimulus. During hematopoietic differentiation, the products of these genes dre differently modulated in 1the erythroid (E), megakaryocytic (Mk), granulocytic (G) or monocytic (Mo) linedge. Bcl-2 supports E, Mo and Mk lineage until terminal differentiation. Bag-1 is specifically maintained in the G lineage, and rapidly lost in E, Mk and Mo, whereas bcl-x is preferentially expressed in the E lineage. With respect to Fas/Fas Ligand (FasL) system. Fas is sustainedly expressed on HPCs and its expression is maintained during E, G and Mo differentiation, while a progressive decline is observed during Mk differentiation. Molecular crosslinking of Fas reduces the rate of cell division of HPCs differentiating along the E and G lineage, while the growth of Mo and Mk series is essentially unaffected. Importantly, triggering of Fas is able to delay Mk, but not G and Mo maturation and to arrest the majority of E cells at the erythroblast basophilic stage. Following Fas stimulation, Mo and Mk cells, as well as quiescent HPCs, do not undergo apoptosis, while E and G cells do. By contrast, the high expression of bcl-2 and bcl-x in E, and bag-1 in G lineage, does not protect from Fas-induced apoptosis. FasL is massively produced by the G lineage during late differentiation, while its expression in the other hematopoietic lineages is either very low or absent, suggesting a potential role of maturating myelocytes/granulocytes in the regulation of hematopiesis. In conclusion, the interaction of Fas and FasL differentially modulates hematopoietic cell growth, differentiation and apoptosis in different lineages: particularly, the Fas/FasL system may represent a key mechanism regulating the balance between effective and uneffective hematopoiesis through the E and G fineage.