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Several with wild-type CD79B and mutant MYD88 did not respond buy diltiazem 180 mg with amex, suggest- randomized studies of R-CHOP with or without bortezomib in ing a MYD88-independent pathway for NF- B activation cheap 60mg diltiazem overnight delivery. Patients untreated DLBCL patients have been initiated. As a single agent, lenalidomide demonstrated a PKC is a serine/threonine kinase amplified through the BCR response rate of 55% in patients with ABC DLBCL compared with signaling pathway that may also play an essential role in the only 9% in patients with GCB DLBCL, suggesting differential activation of the NF- B pathway in B cells (Figure 4). Enzastaurin is a potent oral inhibitor of PKC that has been IRF4, which requires the expression of the E3 ubiquitin ligase studied in relapsed/refractory DLBCL and in combination with complex coreceptor protein cereblon. R-CHOP in patients with intermediate- and high-risk DLBCL. It is also important to understand and target upstream targets involved in NF- B activation (Figure 3). Chronic BCR signaling and activating Studies have also targeted the PI3K/AKT/mTOR signaling pathway mutations of CARD11 and MYD88 promote NF- B activation, using mTOR inhibitors. Although the patients have been heteroge- suggesting several targets. One potential target is Bruton tyrosine neous, mTOR inhibitors (temsirolimus and everolimus) have in- kinase (Btk), in which the selective inhibitor ibrutinib is selectively duced complete remissions across lymphoma subtypes. BCR and MYD88 signaling pathways and potential targets. Signaling also activates the AKT/MTOR and MAP kinase pathways. Constitutive MYD88 signaling is an alternative pathway leading to NF- B activation. Although GCB DLBCL has a better prognosis than ABC DLBCL, Although the ideal target for the PI3K/AKT/mTOR pathway is upwards of 30% of patients are not cured with R-CHOP–based unknown, investigators are targeting upstream molecules such as treatment (Figure 1A). Bcl-6 is a key transcription factor expressed AKT and PI3K. GS 1101 is a potent small-molecule inhibitor of by GCBs, including GCB DLBCL, that regulates cell growth and PI3K p110 that blocks constitutive PI3K signaling in vitro. Bcl-6 suppresses genes that are involved in lymphocyte 1101 was studied in 9 patients with DLBCL and was well tolerated, activation, differentiation, and cell cycle arrest and the DNA but did not result in clinical responses. In GCB DLBCL, chromo- somal translocations affecting the Bcl-6 locus juxtapose heterolo- Alternative activation of the classical NF- B signaling pathway gous promoters from the partner chromosome with intact Bcl-6 occurs through stimulation of MYD88 (Figure 3). MYD88 muta- coding sequences, leading to deregulated expression of Bcl-6; in tions are present in 30% of ABC DLBCL cases and promote NF- B addition, Bcl-6 can be altered by multiple somatic mutations. These activation through this pathway via the kinase activity of IRAK1 mutations/translocations in Bcl-6 enhance its inhibitory effect on and IRAK4. In ABC DLBCL cell lines, it is the activity of IRAK4 the apoptotic stress response and promote proliferation, both of but not IRAK1 that is required for the oncogenic effect of MYD88. These results suggest Small-molecule inhibitors of IRAK4 have demonstrated selective that BCL6 is an important target for GCB DLBCL. BCL6 is difficult toxicity for ABC DLBCL cell lines and represent another potential to target directly. Recently, a small molecule known as the 79-6 therapeutic target in ABC DLBCL. A potentially important observation is the effect of topoisomerase II inhibition on Bcl-6 expression. Inhibition of topoisomerase II by etoposide leads to the down-regulation of Bcl-6 expression through ubiquitin-mediated protein degradation and possibly transcriptional inhibition. This raises the possibility that inhibition of topoisomerase II may be important in GCB DLBCL and may partially explain the finding by the German cooperative group (DSHNHL) that the addition of etoposide to CHOP (CHOEP) Figure 4. Blockade of BCR signaling in ABC DLBCL with ibrutinib, improved the event-free survival (EFS) of younger patients, who an irreversible inhibitor of BTK. Shown is the pilot analysis of ABC have a higher incidence of GCB DLBCL compared with older DLBCL gene mutations and response to ibrutinib. In GCB DLBCL, bcl-2 expression is associated with suggest that topoisomerase inhibition is important. In this regard, the recently, Gascoyne et al published a study showing that the con- DA-EPOCH-R regimen inhibits topoisomerase II through several current protein expression of MYC and BCL-2 had an adverse strategies: (1) it incorporates 2 topoisomerase II inhibitors, etopo- outcome, whereas expression of either alone did not portend a worse side and doxorubicin; (2) it optimizes topoisomerase II inhibition outcome with R-CHOP. There is a virtual absence of prospective studies in PMBL, which has led to conflicting findings and a lack of treatment standards. The polycomb-group oncogene EZH2 has now been reported as a Nonetheless, several observations have emerged from the literature. EZH2 is an epigenetic control with standard immunochemotherapy, necessitating routine regulator gene and mutant EZH2 protein results in decreased mediastinal radiotherapy.

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