Studies indicate that the ��leukemia microenvironment�� supports acute lymphoblastic leukemia cells developing in the bone marrow , namely by providing survival/proliferation signals and by functioning as potential niches for chemotherapy-resistant tumor cells. Ligands and receptors of the tumor-necrosis factor superfamily play significant roles in 957054-30-7 B-cell development and homeostasis. B-cell-activating factor is a TNFsuperfamily member expressed by various cell types ], and has been shown to prolong B-cell survival. BAFF transgenic mice exhibit increased number of B-cells, expressing MK-1775 Wee1 inhibitor elevated levels of anti-apoptotic molecules. In addition to serving as a potent B-cell survival factor, BAFF also functions as a costimulator of B-cell proliferation. BAFF shares significant homology with APRIL . Three known receptors for BAFF 2 BCMA , TACI and BAFF-R have been identified, which are expressed by immature/ mature B-lymphocytes. BCMA and TACI also bind APRIL, whereas BAFF-R exclusively interacts with BAFF. The role of BCMA in B-cell homeostasis remains undefined: whereas injection of BCMA-Ig, as decoy receptor, resulted in marked B-cell reduction in secondary lymphoid organs, BCMA-deficient mice did not exhibit an obvious phenotype. TACI-null mice showed elevated B-cell numbers, suggesting a negative regulatory role for TACI on B-cell homeostasis; TACI-Ig administration also led to inhibition of T-cell-independent immune responses, abolition of germinal center formation and prolonged B-cell lifespan. The phenotype of BAFF-Rdeficient mice is similar to that of BAFF-deficient mice, with impaired B-cell maturation beyond the T1 stage, decreased Ig levels and decreased T-cell-dependent and T-cell-independent immune responses. This suggests that the BAFF/BAFFR axis is the main driver for B-cell survival and maturation. . The mechanisms regulating BAFF-system molecule expression are poorly understood. Interleukin-10, Interferon-a , IFN-c and CD154/CD40L can upregulate BAFF or APRIL expression in different cells, including macrophages/monocytes and dendritic cells. During malignant transformation, cells undergo genetic/epigenetic alterations that drive changes in their proteome, such as over-expression or aberrant expression of critical molecules. APRIL, which is expressed at low levels by normal cells, is upregulated on B-cell chronic lymphocytic leukemia , lymphoma and myeloma cells , i.e. malignancies involving late-stage B-cells. BAFF is expressed by malignant mature B-cells, in contrast to their normal counterparts.