B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with an immunophenotype expressing the T-cell marker CD5 together with CD19, CD20, CD23, and dim-surface immunoglobulin. 1 Although immunophenotypically similar to the normal B1 lymphocytes, CLL cells have a distinct mRNA gene expression profile that most approximates a postgerminal memory B cell. 2 For many years CLL has been viewed as a nonproliferating leukemia based on the nonproliferating blood compartment; however, as with normal B cells, it has come to be recognized that CLL cell proliferation probably occurs in sites where microenvironmental stimulation occurs such as the lymph nodes and spleen. In such sites, proliferation centers are observed with a high proportion of dividing CLL cells expressing survivin that are often surrounded by either T cells or accessory stromal cells capable of providing cytokine costimulation. 3,4 Studies administering heavy water allow accurate measurement of all body compartments of CLL and assess the birth rate of CLL tumor cells in vivo. 5 These studies have demonstrated a broad range of proliferation of CLL cells that varies based on disease state and also immunoglobulin heavy chain variable (IVGH) mutational status. 5,6 In particular, a higher tumor birth rate is noted in CLL patients with IVGH unmutated disease and ZAP-70 expression. Multiple studies have documented evidence of enhanced B-cell receptor (BCR) signaling in patients with IVGH unmutated disease or those with increased ZAP-70 expression. [7][8][9] Thus, accessory cytokines, cell-cell contact in the microenvironment, and also BCR-signaling coupled to B-cell proliferation appear sentinel to CLL progression and pathogenesis.While understanding of CLL biology has improved dramatically, until very recently integration of these findings to treatment interventions has been lacking. Specifically, treatment has included alkylators, nucleoside analogs, and their combination where small advances in improved response and progression-free survival (PFS) have been noted. 10,11 However, these therapies have had very little impact on overall survival of CLL. The addition of the chimeric CD20 antibody, rituximab, perhaps represents the most significant advance in CLL therapy. Rituximab single agent activity 12 and phase 2 studies combining it with fludarabine (FR) or fludarabine and cyclophosphamide (FCR) have demonstrated improved overall survival (OS) over historical controls. 13,14 A randomized trial of FCR versus fludarabine or cyclophosphamide alone 15 demonstrated significant improvement in response; PFS and OS. While the presumptive mechanism of rituximab in CLL has been assumed to be immunologic (reviewed in Jaglowski and Byrd 16 ), a recent study demonstrated a direct effect on BCR-signaling in both normal and malignant B cells via perturbation of membrane rafts by CD20 anti...

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Receptor interacting protein-2 (RIP2) is a caspase recruitment domain (CARD)-containing kinase that interacts with caspase-1 and plays an important role in NF-κB activation. Apoptosis-associated speck-like protein containing a CARD (ASC) is a PYRIN and CARD-containing molecule, important in the induction of apoptosis and caspase-1 activation. Although RIP2 has also been linked to caspase-1 activation, RIP2 knockout animals fail to show a defect in caspase-1-mediated processing of proIL-1β to its active form. Therefore, RIP2 function in binding to caspase-1 remains poorly understood. We hypothesized that caspase-1 may serve as a scaffolding molecule that promotes RIP2 interaction with IκB kinase-γ thus inducing NF-κB activation. We further hypothesized that ASC, which also interacts with caspase-1 via its CARD, may interfere with the caspase-1 RIP2 interaction. In HEK293 cells, ASC induced prominent activation of caspase-1 and proIL-1β processing. RIP2 transient transfection induced transcription of an NF-κB reporter gene. This RIP2-induced NF-κB activity and caspase-1 binding was inhibited in a dose-dependent fashion by ASC. Consistent with a role for caspase-1 as a scaffold for RIP2, caspase-1 knockout macrophages were suppressed in their ability to activate NF-κB, and septic caspase-1 knockout animals produced less IL-6, a functional marker of NF-κB activity. Lastly, THP-1 cells treated with small interfering RNA for ASC decreased their caspase-1 activity while enhancing their NF-κB signal. These data suggest that ASC may direct caspase-1 away from RIP2-mediated NF-κB activation, toward caspase-1-mediated processing of proIL-1β by interfering with the RIP2 caspase-1 interaction.