ALBERT

Description: Abstract 3152 We have reported that treatment of B-NHL cell lines with rituximab resulted in the inhibition of the constitutively activated PI3K-AKT pathway (Suzuki et al., Oncogene 26:6184, 2007). Examination of the mechanism by which rituximab inhibits the PI3K/Akt pathway revealed that it induces the expression of the PI3K/Akt inhibitor PTEN (phosphatase and tensin homolog detected on chromosome 10). Time kinetic analysis indicated that the induction of PTEN occurs as early as 6 h post-rituximab treatment. The objective of this study is to delineate the molecular mechanism by which PTEN is induced by rituximab. We hypothesized that rituximab-induced inhibition of the constitutively activated NF-κB pathway, directly and indirectly through inhibition of the PI3K/Akt pathway, may result in the inhibition downstream of the PTEN transcription factors and repressors, Snail and Yin Yang 1 (YY1). Snail has been reported to repress the transcription of PTEN (Escriva, M et al., Mol Cell Biol 28:1528, 2008). Also, YY1 has been reported to positively regulate Snail transcription and expression (Palmer, MB et al., Mol Cancer Res 7:221, 2009). In addition, the induction of PTEN by rituximab also results, in a feed-back loop, in the suppression of YY1 and Snail and potentiates the induction of PTEN (Petriella et al, Cancer Biology Therapy, 8, 1389, 2009). This hypothesis was tested using the B-NHL Ramos cells, as model, for these studies. Treatment of Ramos with rituximab (20ug/ml for 16 hours) resulted in the inhibition of NF-κB, Snail, and YY1 and induction of PTEN expression as assessed by western. The direct role of Snail and YY1 in the suppression of PTEN expression was demonstrated in cells transfected with Snail or YY1 siRNA. The treated cells demonstrated significant induction of PTEN and, concomitantly, inhibition of the PI3K/Akt pathway. We have reported that rituximab sensitizes B-NHL cells to apoptosis by various chemotherapeutic drugs and demonstrated that inhibition of the PI3K/Akt pathway by various inhibitors mimics rituximab in the sensitization of the tumor cells to apoptosis by chemotherapeutic drugs (Suzuki et al., Oncogene 26:6184, 2007). The role of PTEN induction by rituximab in the sensitization of resistanr B-NHL cells to drug-apoptosis was demonstrated in cells pre-treated with rituximab (to induce PTEN) and then transfected with PTEN siRNA. The transfected cells were resistant to drug-induced apoptosis compared to the control siRNA treated cells. Altogether, the above findings demonstrate that rituximab-induced inhibition of the PI3K/Akt pathway is due, in part, to the induction of PTEN through rituximab-induced inhibition of the PTEN repressors Snail and YY1, downstream of NF-κB. Thus, the induction of PTEN by rituximab plays a major role in the reversal of tumor cell resistance to chemotherapeutic drugs. Further, the findings reveal that the dysregulated PI3K/Akt/NF-κB/Snail/YY1/PTEN loop in B-NHL cells can be interfered by rituximab. This interference leads to the inhibition of cell survival and reversal of resistance through sensitization to drugs. We propose that the gene products in this loop are potential novel therapeutic targets in the treatment of lymphoma. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 455 Functional B cell and plasma cell immune responses are dependent upon an exquisitely controlled process integrating signals from activating and inhibitory receptors present on the surface of these cells. These activating and inhibitory signaling pathways regulate both the quality and quantity of immunoglobulin (Ig) production. These signaling motifs, termed immunoreceptor tyrosine-based activation motif (ITAM) and ITIM provide the basis for two opposed signaling modules that duel for control of plasma cellular activation within the immune system. The inhibitory Fc receptor FcγRIIb is expressed on plasma cells and controls their persistence in the bone marrow and their ability to produce most serum Ig. Activation of FcγRIIb leads to the phosphorylation of ITIM and recruitment of SH2-containing protein tyrosine phosphatase-1 (SHP-1) SHP-2 and the SH2-containing inositol 5-phosphatase (SHIP) in plasma cells. FcγRIIb-mediated SHIP phosphorylation results in enhanced degradation of PtdIns (3,4,5)P, which is required for B-cell antigen receptor (BCR)-induced recruitment and activation of downstream ITAM signaling molecules. The inhibitory IgG Fc receptor FcγRIIB was the first discovered and remains the best studied example of an ITIM-containing receptor. In this study, we first investigated the IgG-binding ability of 18 MM patients and 10 normal donors to FcγRIIb using flow cytometric analysis. Each serum sample was incubated with MHC1 cells that only express FcγRIIb but do not express FcγRI and FcγRIIa. After washing three times with 1 × PBS, anti-human IgG antibody conjugated with FITC was added to the cells for another 30 minutes. The results showed MM patients' serum IgG have much lower FcγRIIb-binding ability than normal human IgG (P

Description: Abstract 4068 Several members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 have been implicated in regulating signal transduction from various TRAF family members. However, the unique biological function of TRAF6 is largely determined by its TRAF-C domain, which does not interact with peptide motifs that are recognized by TRAF1, -2, -3 or -5. We have reported inhibition of MM cell proliferation and increase of apoptosis through regulation of the NF-κB and JNK pathways through silencing TRAF6 C-domain mRNA and the dominant negative peptide expression vector (Chen H. et al, Oncogene, 2006; Li M. et al, Blood 2009). TRAF6 have been recently found as a ligase for Akt ubiquitination (Yang WL et al, Science, 2009). Akt signaling plays a central role in many biological functions, such as cell proliferation and apoptosis. In this study, we first investigated whether TRAF6 is over-expressed in MM tumor cells. Twelve MM fresh bone marrow (BM) aspirates derived from MM patients were assessed using Western blot analysis and immunohistochemical staining with anti-TRAF6 antibody. We found that TRAF6 protein was highly expressed in tumor cells from MM patients compared to normal human BM samples. Based on TRAF6, CD40, and RANKL sequences and crystal structures, we targeted the TRAF6 C-domain binding residues. We found that TRAF6 dominant negative binding peptide (TRAF6dn) significantly inhibited MM cell proliferation maximally at 72 hours using the MTS cell proliferation assay whereas effects on inducing MM cell apoptosis were most prominent at 48 hours as assessed with Annexin V staining with flow cytometric analysis. The decrease in cell proliferation and increase in cell apoptosis occurred in a concentration peptide-dependent fashion. Furthermore, phosphorylation of both AKT and NF-κB were also reduced using our human TRAF6dn or decoy peptides. We also examined the effect of the TRAF6dn peptide on the JNK pathway since this signaling pathway is also associated with cell cycle effects in MM. We measured JUN kinase kinase (JNKK), which activates the MAP kinase homologues SAPK and JNK in response to IL-1 receptor stimulation. The results showed that the phosphorylation of JNKK is markedly reduced after treatment with the TRAF6dn peptide. Furthermore, we examined c-Jun, a component of the transcription factor complex AP-1, which binds and activates transcription at TRE/AP-1 elements. We evaluated the effect of TRAF6dn peptide on osteoclast formation using cells from human monocytes isolated by anti-CD14 micro-bead affinity column from MM patients' BM or peripheral blood mononuclear cells. The monocytes were cultured on slide-culture dishes (2 × 105 cells/well).We found TRAF6dn markedly inhibited osteoclast cell formation from monocytes induced with RANKL and mCSF in a concentration- dependent fashion compared with a control group using tartrate resistant acid phosphatase staining. We further assessed whether TRAF6dn can reduce bone resorption using a dentin bone resorption assay. BM-derived monocytes were isolated as above and were cultured on dentin bone slides (4 × 105 cells/slide). The cells treated with a TRAF6dn peptide or the control peptide, were incubated with 50ng/ml RANKL and 10ng/ml MCSF. All cells were cultured for 21 days. It was found that TRAF6dn significantly inhibited lacunar resorption in a concentration-dependent fashion. These studies suggest that TRAF6 is over-expressed in MM and our TRAF6dn peptide inhibits many signaling pathways critical to the growth of MM and formation of osteoclasts resulting in marked anti-MM effects and reduction in osteoclast formation resulting in marked inhibition of bone resorption. Thus, this novel approach may offer a new therapeutic approach to both treat multiple myeloma and reduce the clinical consequences resulting from enhanced bone loss that commonly occur in these patients. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4067 Although patients with multiple myeloma (MM) initially respond to current treatment modalities, it remains an incurable disease. Many new therapeutic options have become available during the past several years but nearly all patients develop resistance to currently available therapeutic options. In addition, there is no tumor marker that is uniformly expressed in all MM cells although CD138 is considered to be present on the surface of tumor cells in most cases of MM but generally is only present in a subset of the patients' tumor population and may be absent in the most resistant part of the tumor clone. In order to address these unmet clinical needs, we queried Compugen's MED Platform, an expression database which covers over 40,000 microarray experiments, for genes overexpressed in B cell-derived malignancies including MM and that exhibit low expression levels in normal cells and tissues. One of the most prominent candidates was CGEN-928, which was validated as over-expressed in MM at the mRNA level using an independent panel of both hematological malignancies and normal tissues. In this study, we first investigated whether the previously unidentified membrane antigen CGEN-928 is expressed in cells from human MM cell lines, human MM xenografts and fresh bone marrow (BM) aspirates derived from MM patients using flow cytometric analysis and immunohistochemical staining with the anti-CGEN-928 TM21 polyclonal antibody (Compugen Ltd, Tel Aviv, Israel). Using this antibody, we found that CGEN-928 was highly expressed in cells from the MM1s, U266 and RPMI8226 MM cell lines. Next, we examined CGEN-928 antigen expression in fresh tumor cells from BM aspirates from 17 MM patients and also showed high expression of CGEN-928. Notably, expression of this antigen was not only found on CD138+ MM cells but also on MM tumor cells lacking CD138 expression. We also examined the expression of CGEN-928 using our human MM xenograft models LAGκ-1A (bortezomib-sensitive), LAGκ-1B (bortezomib-resistant) and LAGλ-1 (melphalan-resistant). The bortezomib-sensitive MM tumor LAGκ-1A expresses CD138 whereas the bortezomib-resistant version LAGκ-1B developed from the same patient after the patient developed bortezomib reisistance does not express CD138. Cells from all three tumor types showed high levels of reactivity with the TM21 antibody. Similar to the fresh MM BM samples, CGEN-928 expression was not only found on CD138+ MM cells but also on CD138- tumor cells derived from these human MM xenografts. Because this molecule is highly expressed on MM cells, we hypothesized that the anti-CGEN-928 antibody may show anti-MM effects and enhance the anti-MM effects of other anti-MM drugs. To evaluate this, we examined the effect of the TM21 antibody alone and in combination with dexamethasone, melphalan and bortezomib in vitro using cell proliferation MTT assays. Anti-TM21 polyclonal antibody (100 mg/ml) decreased MM tumor cell proliferation and increased apoptosis in cells from the MM1s, RPMI8226 and U266 cell lines. Next, we determined the effects of combining the anti-CGEN-928 antibody with bortezomib, melphalan or dexamethasone on MM1s cells. Cell proliferation assays demonstrated marked enhanced anti-proliferative effects when CGEN-928 antibody at concentrations of 5, 10, 50 and 100 mg/ml was combined with bortezomib, melphalan or dexamethasone. Further investigations are defining the mechanisms and signal transduction pathways that produce the anti-MM effects of CGEN-928. These preliminary studies suggest that the CGEN-928 antigen is highly expressed in MM and treatment with an anti-CGEN-928 polyclonal antibody produces anti-MM effects alone and in combination with other anti-MM agents; and thus, this antigen may be a target for the treatment of multiple myeloma. Currently, a monoclonal anti-CGEN-928 antibody is in development that will be used by our group to evaluate its anti-MM effects both in vitro and in vivo using our SCID-hu models of human MM. Disclosures: Levy: Compugen Ltd.: Employment. Dassa:Compugen Ltd.: Employment. Cojocaru:Compugen Ltd.: Employment. Berenson:Compugen Ltd.: Research Funding. Levine:Compugen Ltd.: Employment.

Description: Abstract 5015 Lyn is a member of the Src kinase (SFK) family and controls the activation threshold of multiple signaling pathways in different types of cells, including B cells (Yamanashi et al., 1989, PNAS). Multiple myeloma (MM) is a hematological malignancy of plasma cells. In MM, Lyn is involved in IL-6-induced cell proliferation (Hallek et al., 1997, Exp Hematol). As one of the most important growth and anti-apoptotic factors for MM cells, both the IL-6/STAT3 and IL-6/ERK pathways have been shown to promote MM cell proliferation and prevent apoptosis. However, STAT3 and ERK activation is not sufficient for IL-6-induced proliferation, which further requires the activation of SFK (Ishikawa et al., 2002, Blood). IL-6-induced proliferation of U266 myeloma cells has been reported to be significantly suppressed following exposure to Lyn-specific antisense oligonucleotides or a Src kinase inhibitor (Ishikawa et al., 2002, Blood). Therefore, a Lyn specific inhibitor, either alone or in combination with other anti-MM drugs, may be a more effective regimen for the treatment of MM. INNO-406 is a novel inhibitor of ABL as well as Lyn. In laboratory-based studies, it has shown anti-tumor activity in hematological malignancies, especially in leukemia cells harboring BCR-ABL mutations (Kimura et al., 2005, Blood). Since Lyn is involved in MM cell proliferation, targeting Lyn may be an alternative therapeutic approach and improve the efficacy of other anti-MM agents. Thus, we conducted this study in order to determine the anti-MM effects of INNO-406. First, Western blot analyses demonstrated that Lyn was expressed in all MM cells analyzed, including bone marrow (BM) mononuclear cells derived from MM patients and MM cells from LAGκ1A, LAGκ1B and LAGκ2 xenografts, three of our unique in vivo SCID-hu models of human MM, which were originally developed from MM patient BM biopsies and have been maintained in SCID mice. However, Lyn activation, as demonstrated by phosphorylation of its downstream molecule HS1, was infrequently found in MM cells. INNO-406 inhibited the growth of the three MM cell lines tested including RPMI8226, U266 and MM1S. Interestingly, the U266 cell line is most resistant to INNO-406 among the three MM cell lines tested although its Lyn activation and expression level is the highest. Apoptosis analysis using flow cytometric analysis following Annexin V staining demonstrated that INNO-406 induced apoptosis in MM cells. When combined with melphalan, doxorubicin or bortezomib, INNO-406 synergistically inhibited MM cell growth. We are currently studying the molecular mechanisms of INNO-406's anti-MM effect, either alone or in combination treatment, and validating our in vitro findings using our unique in vivo mouse models of human MM. Updated data from these additional studies will be reported at the meeting. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4066 Introduction: Although we have previously demonstrated the anti-myeloma (MM) effects of the novel proteasome inhibitor (PI) CEP-18770 alone and the ability of this PI to enhance the anti-MM effects of melphalan as well as another PI bortezomib (Sanchez et al. Br J Haematol, 148(4):569-581 [2010]), this novel PI has not been evaluated in combination with immunomodulatory agents (IMiDs) or glucocorticosteroids. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which have led to the successful use of these combinations to treat patients with MM. Thus, we conducted these studies to ascertain the anti-MM effects of CEP-18770 in combination with the glucocorticosteroid dexamethasone (DEX) and/or IMiD lenalidomide (LEN) in vivo using our human SCID (severe combined immunodeficient)-hu MM, LAGk-1B (bortezomib-resistant tumor). Methods: Each naïve SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were randomized into treatment groups. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μ l) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 3 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. Mice were treated with 30 mg/kg of this IMiD daily via oral gavage. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated with 1.25 mg/kg daily of this glucocorticosteroid via intraperitoneal (i.p.) injection. Tumor size was measured using standard calipers on a weekly basis (n=9–10 mice/group). Results: At day 28 post-tumor implantation, mice receiving CEP-18770 plus daily DEX markedly inhibited tumor volume growth (P=0.0007), compared to mice receiving vehicle, whereas CEP-18770 alone did not show a significant effect, but by day 35 both CEP-18770 administered alone and in combination with DEX significantly inhibited tumor volume growth (P 〈 0.0001) compared to mice receiving vehicle. Notably, DEX alone had no anti-MM activity at any time point throughout study duration. Overall, mice survived the DEX, CEP-18770, and CEP + DEX treatment regimens well with 9/10, 10/10, and 10/10 mice alive, respectively, at study termination (day 35). Similarly, at day 28 post-tumor implantation, mice receiving CEP-18770 plus daily LEN showed markedly smaller tumors compared to mice receiving vehicle (P=0.0004), whereas CEP-18770 alone did not show an effect. However, by day 35, both CEP-18770 administered alone (P 〈 0.0001) and the combination of CEP-18770 + LEN (P 〈 0.0001) significantly inhibited tumor volume growth compared to mice receiving vehicle alone. LEN alone showed no anti-MM activity at any time point throughout the study. Overall, mice survived the CEP-18770, LEN, and CEP + LEN treatment regimens well with 10/10, 10/10, and 9/10 mice alive, respectively, at study termination (day 35). The anti-MM effects of the triplicate combination of CEP-18770 + DEX + LEN in LAGk-1B-bearing mice was also evaluated. At day 28 and day 35, the triplicate combination also produced markedly smaller tumor volumes (P=0.0001) compared to vehicle-treated mice. However, this was not significantly different from single agent CEP-18770 or the combination of this PI with DEX or LEN. Overall, mice survived the triplicate combination regimen well with 9/10 mice alive at study termination (day 35). Conclusions: These in vivo studies using our bortezomib-resistant LAGk-1B SCID-hu model show that CEP-18770 administered alone, in combination with DEX or LEN, or in triplicate combination with both DEX and LEN, resulted in statistically significant tumor volume growth inhibition when compared to vehicle-treated mice. Although initial anti-MM effects were more marked with the combination therapies, with longer follow-up single agent CEP-18770 produced similar anti-tumor effects as the CEP-18770-containing doublet and triplicate combinations. Furthermore, the toxicity profile was favorable and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. These results provide further support for the development of the novel PI CEP-18770 for the treatment of MM. Disclosures: Berenson: Cephalon, Inc.: Consultancy, Research Funding.

Description: Abstract 5012 Introduction: Although many previous studies from our laboratory and others have used mice bearing human MM to evaluate bortezomib (BORT) alone and in combination regimens, no data exist on the sequential treatment using BORT with conventional anti-MM agents in mice bearing human MM tumors who have progressed from their initial treatment with a variety of anti-MM agents including BORT. In this study, we treated severe combined immunodeficient (SCID) mice bearing one of our human MM tumors LAGκ-1A with single agent bortezomib BORT, melphalan (MEL), dexamethasone (DEX) or pegylated liposomal doxorubicin (PLD) until disease progression and then evaluated subsequent use of combination therapies. Progression was defined as an increase in paraprotein equal to or above 25% compared to the prior time point evaluated 1 week previously. Following progression, LAGκ-1A-bearing SCID mice were assigned to receive no treatment, continue the initial therapy, substitution of initial therapy by another conventional anti-MM agent BORT, MEL, DEX, or PLD, or continue the initial therapy in combination with another anti-MM agent. An untreated control group was also included in these studies. Methods: Tumors were allowed to grow for 7 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into one of five treatment groups. Initial single agent therapy was administered as follows: BORT intravenously (i.v.) twice weekly at 0.5 mg/kg, DEX (1.25 mg/kg) daily by intraperitoneal (i.p.) injection, MEL i.p. weekly at 1.5 mg/kg, or PLD 0.2 mg/kg on three consecutive days weekly by i.p. injection. Following disease progression, mice were randomized into one of the above mentioned treatment groups. Tumor size and IgG levels were measured using calipers and a hIgG specific immune assay on a weekly basis. Results: Following progression from single-agent BORT, mice treated with the combination of BORT + DEX or DEX alone showed similar anti-MM effects. In contrast, after mice progressed from single-agent DEX, BORT alone did not show significant anti-MM effects compared to mice continued on DEX alone or who received no further treatment whereas the addition of BORT to DEX produced a marked anti-MM effect. Following disease progression from MEL treatment alone, treatment with BORT alone or in combination with MEL produced similar anti-MM activity. However, among mice progressing from single agent BORT, the addition or substitution with MEL showed no anti-MM effects; and in fact, reduced the efficacy of BORT when compared to mice remaining on the drug alone following disease progression. Following disease progression from single agent PLD treatment, BORT therapy alone showed anti-MM effects; however, the addition of BORT to PLD did not show any anti-MM activity. In addition, mice progressing from BORT treatment alone who then received either PLD alone or in combination with BORT actually showed enhanced tumor growth compared to continuing BORT alone. Conclusions: Results from these in vivo studies using our SCID-hu models of human MM suggest that the sequencing of drugs following progression from initial therapy has a dramatic impact on responsiveness of the human myeloma cells growing in SCID mice. These studies suggest that this approach can be used to optimize in what order and specific combinations of anti-MM drugs should be administered following disease progression which should improve outcomes for patients with MM. Disclosures: Hilger: Millennium Pharmaceuticals, Inc.: Employment. Hibner:Millennium Pharmaceuticals, Inc.: Employment. Berenson:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Abstract 2887 Galiximab (anti-CD80 mAb) is a primatized mAb (human IgG1 constant region and Cynomogous macaque variable region) that binds CD80 on lymphoma cells. It has been shown in vitro that Galiximab inhibits tumor cell proliferation and mediates ADCC. Galiximab is currently in clinical trials for a variety of cancers. Our preliminary findings demonstrated that Galiximab treatment of B-NHL cell lines, like Raji, triggers the cells and inhibits the constitutively activated NF-κB pathway. We hypothesized that Galiximab-induced inhibition of NF-κB may result in the inhibition downstream of several anti-apoptotic gene products and sensitizes cells to drug-induced apoptosis. Raji cells were treated with Galiximab (20-100 μg/ml) for 18h and followed by treatment with the chemotherapeutic drug CDDP (5-10 μg/ml) for 24h and apoptosis was determined by flow for activation of caspase 3. The findings demonstrated that the cells treated with Galiximab were sensitized to CDDP-induced apoptosis. Analysis of the apoptotic pathway following treatment with Galiximab revealed the inhibition of anti-apoptotic gene products such as Bcl-2 and Bclxl. We have also found that Galiximab, like rituximab, inhibits the Fas and DR5 transcription repressor Yin Yang 1 (YY1) and the direct inhibition of YY1 resulted in tumor cell sensitization to both Fas-L and TRAIL. We examined whether inhibition of YY1 by Galiximab was also involved in the sensitization to CDDP apoptosis. Raji cells were treated with YY1 siRNA and, unlike control siRNA or non-treated siRNA cells, the tumor cells were sensitized to CDDP apoptosis. The inhibition of YY1 by siRNA correlated with the inhibition of Bcl-2 and Bclxl. The direct role of Bcl-2 and Bclxl in the regulation of resistance was corroborated by treatment of cells with the Bcl-2 family inhibitor, 2MMA3, and such cells mimicked Galiximab and were sensitive to CDDP-induced apoptosis. The mechanism by which treatment with YY1 siRNA resulted in the inhibition of Bcl-2 and Bclxl and the reversal of resistance is not clear. We suggest that YY1 inhibition, following Galiximab-induced inhibition of NF-κB, will result in the inhibition of Snail transcription (Palmer, MB et al., Mol cancer Res 7:221, 2009). Inhibition of the RKIP (Raf kinase inhibitor protein) repressor Snail will result in the induction of RKIP (Wu, K and Bonavida, B Crit Rev immu 29:241, 2009) and, in turn, RKIP will inhibit NF-κB and resulting downstream in the inhibition of Bcl-2 and Bclxl. In addition, it has been reported that YY1 negatively regulates p53 (Sui, G et al., Cell 117:889, 2004) and YY1 inhibition by Galiximab will upregulate p53 and which will result in the inhibition of Bcl-2 and Bclxl (see scheme below). The present findings demonstrate that Galiximab sensitizes drug-resistant B-NHL cells to drug-induced apoptosis via modulation of the NF-κB/YY1/Snail/RKIP/p53 loop. Current studies are validating the present findings with freshly-derived B-NHL cells and also examining the molecular mechanism by which YY1 regulates Bcl-2/Bclxl expression and the reversal of resistance. Disclosures: No relevant conflicts of interest to declare.