Tuning the rheostat of the myelopoietic system via Fas and TRAIL.

During the last decade, the concerted effort of numerous scientific groups has expanded our understanding of the finely tuned network present within bone marrow for the regulation of the hematopoietic system. This network, comprising humoral and cellular cross talk, is responsible for the adaptation of hematopoietic populations to demands as they arise. Major components of this control system are death receptors and their specific ligands, which eliminate superfluous cells once they have fulfilled their respective functions.

Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools.

In the past decade, it was concluded from a number of investigations that death domain-containing members of the tumor necrosis factor-receptor (TNF-R) family and their ligands such as Fas/FasL and TNF-related apoptosis-inducing ligand (TRAIL)-R/TRAIL are essential for maintaining an intact immune system for surveillance against infection and cancer development and that nondeath domain-containing members such as CD30 or CD40 are involved in the fine tuning of this system during the selection process of the lymphatic system. In line with this conclusion are the observations that alterations in structure, function, and regulation of these molecules contribute to autoimmunity and cancer development of the lymphoid system. Besides controlling size and function of the lymphoid cell pool, Fas/FasL and TRAIL-R/TRAIL regulate myelopoiesis and the dendritic cell functions, and severe alterations of these lineages during the outgrowth and expansion of the lymphoid tumors have been reported.

Tetrocarcin-A--induced ER stress mediates apoptosis in B-CLL cells via a Bcl-2--independent pathway.

Tetrocarcin-A (TC-A), an antibiotic agent isolated from actinomycetes, has recently been described to antagonize Bcl-2 functions, thereby sensitizing tumor cells to cell death signals under control of Bcl-2. In this study, we analyzed the direct proapoptotic effect of TC-A in the B-chronic lymphocytic leukemia (B-CLL) model. We focused on the signal cascade triggered by TC-A in B-CLL cells and identified activated mitochondrial as well as endoplasmatic reticulum (ER) stress signals.

Stressful death of T-ALL tumor cells after treatment with the anti-tumor agent Tetrocarcin-A.

The T-ALL cell lines CCRF-CEM and Jurkat were studied for their sensitivity toward apoptosis induced by tetrocarcin-A (TC-A), an antibacterial and antitumor agent isolated from the actinomycete Micromonospora. This substance promoted cell death via a mitochondrial signaling pathway, that is, by activation of Bid and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, and activation of effector caspases, even under conditions of Bcl-2 overexpression. Furthermore, sensitivity to TC-A was not dependent on expression of wild-type caspase-8.