The expression of BAFF/APRIL by leukemia BCP suggests the involvement of BAFF-system signaling, via cell-cell contact and/or through autocrine mechanisms. BAFF and APRIL expression was reported in other B-cell malignancies, namely non-Hodgkin��s lymphoma, plasma-cell leukemia and Waldenstrom��s macroglobulinemia; APRIL as a soluble factor, whereas BAFF was detected both as soluble and membrane form. Here, we identified a new APRIL isoform, APRIL-d, lacking the consensus motif for furin convertase-mediated cleavage, which may explain the surface APRIL seen in B-ALL cells. Analyses of genomic sequences showed canonical splicing donor and NVP-BEZ235 acceptor sites in the human gene and in other species . In addition to soluble BAFF, which is elevated in patients�� plasma, leukemia B-cells express membrane BAFF and blockade with BCMA-Fc markedly inhibited basal leukemia cell proliferation, further supporting the involvement of homotypic interactions on the functional role of the BAFF-system in B-ALL. The B-ALL-expressed BAFF-system receptors are functional as they bind BAFF and/or APRIL and their ligation triggers NF-kB, MAPK, and Akt signaling, mediating leukemia cell survival and potentiating their response to CD40L Niraparib PARP inhibitor mitogenic signals. NF-kB and MAPK activation was expected, and sheds light on molecular mechanisms by which BM microenvironmental cues, or at least extrinsic signals, may impact on leukemia BCP. Studies in other Bcell malignancies showed the engagement of NF-kB, MAPK, and Akt by BAFF or APRIL stimulation. Our study unveils the involvement of new molecular axis in the biology of malignant BCP, particularly in the crosstalk between leukemia cells and their supportive BM microenvironment. Eukaryotic cells contain three multi-subunit RNA polymerases that transcribe the nuclear genome and are responsible for the production of selected classes of RNAs . Pol I is responsible for synthesis of the tandem repeated ribosomal RNA genes, Pol II synthesizes mRNA and many non-coding RNAs, and Pol III synthesizes tRNA, 5S rRNA, and few other small untranslated RNAs. These RNA polymerases share 5 subunits, and their catalytic cores are similar to each other and to E.coli RNA polymerase . Unlike bacterial and bacteriophage RNA polymerases that bind specifically to promoter sequences, the eukaryotic enzymes work in conjunction with transcription factors that directly bind promoters and recruit the appropriate RNA polymerase to initiate transcription . The TATA-binding protein is required for transcription by all three RNA polymerases , and it is a component of multi-protein complexes that function specifically with a particular RNA polymerase machinery .