Preclinical activity of the JAK1/2 inhibitor ruxolitinib on malignant plasma cell growth and survival.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18565-e18565 ◽  
Author(s):  
Renate Burger ◽  
Tim Bugdahn ◽  
Matthias Staudinger ◽  
Matthias Peipp ◽  
Andreas Günther ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Thymidine Uptake ◽  
Jak Inhibitor ◽  
Growth And Survival ◽  
Stat3 Phosphorylation

e18565 Background: In multiple myeloma, cytokines in the tumor environment, in particular interleukin-6 (IL-6), support the growth and survival of malignant plasma cells. Binding of IL-6 to its receptor leads to gp130 dimerization and activation of JAKs and STAT3. Ruxolitinib (INC424)is the first small molecule JAK inhibitor approved for the treatment of patients with myelofibrosis. The aim of our study was to evaluate the effects of ruxolitinib on malignant plasma cells. Methods: Cell growth was studied in seven myeloma cell lines including the IL-6 dependent INA-6. Ruxolitinib was tested at 0.0625 µmol/L to 8 µmol/L. Proliferation of plasma cell enriched patient samples was measured by [3]H-thymidine uptake, apoptosis by flow cytometry upon annexin V/7-AAD staining. Levels of STAT3 and ERK1/2 phosphorylation were determined by Westernblot analysis. IC50 concentrations and combination index were calculated with CalcuSyn. IL-6 levels were determined by ELISA. Results: A significant inhibition of plasma cell growth with ruxolitinib was achieved in IL-6 dependent INA-6 cells (IC50 0.22 µmol/L). Complete growth inhibition at 1 µmol/L was seen in the absence and presence of bone marrow stromal cells. Stromal cell viability and IL-6 production were not affected. The number of apoptotic INA-6 cells upon treatment with ruxolitinib at 1 µmol/L increased 3.6- and 7.2-fold (after 48 and 72 hours, respectively), consistent with the reduction of IL-6 induced STAT3 phosphorylation. A similar strong inhibitory activity of ruxolitinib (IC50 0.16 µmol/L) was observed in tumor cells of a patient with plasma cell leukemia proliferating in response to IL-6. In contrast, none of the myeloma cell lines that grow autonomously were sensitive, pointing to the kinase specificity of the drug. Using INA-6 as a model, combinations with other signaling inhibitors revealed additive to synergistic effects with PI3K, mToR and IGF-1R inhibitors. Conclusions: In multiple myeloma, ruxolitinib has a strong cytotoxic activity against malignant plasma cells that require IL-6 for growth and survival. This warrants further clinical testing but also points to the need of identifying molecular markers to predict benefit from JAK inhibitor treatment.

Serum/Glucocorticoid-Regulated Kinase 1 (SGK1) Is a Prominent Target Gene of the Transcriptional Response to Cytokines In Multiple Myeloma and Supports the Growth of Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1915-1915
Author(s):  
Unn-Merete Fagerli ◽  
Thorsten Stühmer ◽  
Toril Holien ◽  
Randi Utne Holt ◽  
Ove Bruland ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factors ◽  
Cell Lines ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Transcriptional Response ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Growth And Survival ◽  
Stat3 Phosphorylation

Abstract Abstract 1915 Multiple myeloma is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We hypothesized that the intracellular signals evoked by cytokines converge and regulate transcription of a set of genes that are common targets for several growth factors and therefore constitute pivotal mediators of the tumor-promoting effects of autocrine or paracrine stimuli. To identify such targets, we determined the changes in gene expression induced by IL-6, TNFalpha, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase SGK1, which is a down-stream effector of PI3-kinase and highly homologous to AKT. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the JAK/STAT pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, shRNA-mediated knock-down of STAT3 reduced basal and induced SGK1 levels, demonstrating the involvement of the JAK/STAT3 signaling pathway in SGK1 induction. Furthermore, down-regulation of SGK1 by shRNAs resulted in decreased proliferation and viability of myeloma cell lines. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their growth and survival and represents an attractive candidate for further evaluation as a therapeutic target. Disclosures: No relevant conflicts of interest to declare.

Inhibition of Interleukin-6 Signaling with CNTO 328 Sensitizes Plasma Cell Dyscrasias to the Effects of Melphalan in Association with Suppression of Signaling through Protein Kinase B/Akt.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1836-1836
Author(s):  
Sally A. Hunsucker ◽  
Valeria Magarotto ◽  
Jairo A. Matthews ◽  
Michael Wang ◽  
Veerabhadran Baladandayuthapani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Cell Lines ◽  
Plasma Cell ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Protein Kinase B ◽  
Myeloma Cell ◽  
Ortho Biotech ◽  
Plasma Cell Dyscrasias

Abstract Abstract 1836 Poster Board I-862 Background: The neutralizing anti-interleukin (IL)-6 monoclonal antibody (MAb) CNTO 328 acts in an additive to synergistic manner to enhance the activity of bortezomib and dexamethasone against models of multiple myeloma by suppressing several IL-6-induced anti-apoptotic signaling pathways. We therefore sought to evaluate the possibility that blockade of IL-6 signaling could also augment the activity of melphalan, and to determine the potential mechanisms underlying this interaction. Methods: A panel of myeloma cell lines was studied both in suspension and with bone marrow stromal cells to evaluate the activity of CNTO 328 with and without melphalan. The CNTO 328 + melphalan combination was also tested in primary cells from patients with a variety of plasma cell dyscrasias. Results: Treatment of IL-6-dependent KAS-6/1, INA-6, and ANBL-6 myeloma cell lines with CNTO 328 + melphalan reduced plasma cell viability in an additive-to-synergistic manner compared to melphalan with a control MAb. Isobologram analysis demonstrated that the combination was synergistic in KAS-6/1 cells regardless of the sequence of drug treatment (combination indices (CIs) from 0.275-0.607), although the strongest synergy was seen with CNTO 328 pretreatment (CIs from 0.275-0.493). These anti-proliferative effects were accompanied by an enhanced activation of drug-specific apoptosis, and this increased cell death was not rescued by the trophic effects of co-culture of plasma cells with the human-derived stromal cell line HS-5. CNTO 328 increased melphalan-mediated induction of both extrinsic, caspase-8-mediated apoptosis, as well as intrinsic, caspase-9-mediated death, which converged to produce increased levels of caspase-3 activity. Apoptosis was enhanced in part by CNTO 328-stimulated cleavage of Bid to tBid, and alterations in the phosphorylation status of BimEL, as well as increased conversion of Bak and, to a lesser extent, of Bax, to their active forms. Neutralization of IL-6 by CNTO 328 also suppressed signaling through the protein kinase B/Akt pathway, as evidenced by decreased levels of phospho-Akt, and decreased activation of several downstream Akt targets, including p70 S6 kinase and 4E-BP1. Importantly, CNTO 328 + melphalan showed enhanced anti-proliferative effects compared to melphalan and a control MAb against primary CD138+ plasma cells derived from patients with multiple myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis, while demonstrating less toxicity to stromal cells. The enhanced effect of the CNTO 328 + melphalan combination was statistically significant compared to either drug alone (p<0.05) in CD138+ cells isolated from patients who had not received prior melphalan therapy. Conclusions: These studies provide a rationale for translation of CNTO 328 into the clinic in combination with melphalan-based therapies, including either high dose therapy in transplant-eligible patients, or standard dose melphalan-containing induction regimens in transplant-ineligible patients, such as with the combination of bortezomib, melphalan, and prednisone. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Xie:Centocor Ortho Biotech Inc.: Employment. Cornfeld:Centocor Ortho Biotech Inc.: Employment. Nemeth:Centocor Ortho Biotech Inc.: Employment.

The Immunotoxin HM1.24-ETA′ Is a Potent Inducer of Apoptosis in Malignant Plasma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3658-3658
Author(s):  
Matthias Staudinger ◽  
Anja Muskulus ◽  
Renate Burger ◽  
Andreas Guenther ◽  
Roland Repp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Annexin V ◽  
Myeloma Cell ◽  
Parp Cleavage ◽  
Single Chain ◽  
Potent Inducer ◽  
Promising Target

Abstract Despite new treatment modalities, the clinical outcome of at least a subgroup of patients with multiple myeloma (MM) still needs improvement. Antibody-based targeted therapies are increasingly used for tumor therapy, and may represent interesting options for MM patients. HM1.24 is a surface molecule that is over expressed on malignant plasma cells and efficiently internalized from the cell surface. It may represent a promising target for the development of myeloma-directed immunoconstructs. Here, the development and characterization of a novel single-chain immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of an HM1.24-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). The immunotoxin was expressed in E. coli and purified to homogeneity by affinity chromatography. Specific binding to HM1.24 was demonstrated by immunofluorescence staining and flow cytometry using antigen positive and negative cells. HM1.24-ETA′ efficiently inhibited growth of IL-6 dependent and IL-6 independent myeloma cell lines (INA-6, RPMI8226, U266). Half maximal growth inhibition was observed at low nanomolar concentrations. Further analyses demonstrated that target cell killing occurred via induction of apoptosis, as evidenced by Annexin V/propidium iodide staining and detection of PARP cleavage. The cytotoxic effect was completely blocked by adding excess of unconjugated parental antibody, demonstrating that the effect was antigen-specific and not mediated by non-specific uptake of the immunotoxin. Importantly, HM1.24-ETA′ efficiently triggered apoptosis (>80% Annexin V positive cells) of freshly isolated plasma cell leukemia cells within 48h. In conclusion, HM1.24-ETA′ efficiently triggered apoptosis of multiple myeloma cell lines as well as freshly isolated tumor cells. These results indicate that HM1.24 may represent a promising target structure for efficient antigen-specific delivery of cytotoxic compounds to plasma cell tumors.

A Novel Role for Histone Deacetylase 11 (HDAC11) in B Cell Lymphopoiesis and Plasma Cell Survival in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4715-4715
Author(s):  
Jason B. Brayer ◽  
Eva Sahakian ◽  
John Powers ◽  
Mark B Meads ◽  
Susan Deng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Myeloma Cell ◽  
Resistant Cell ◽  
Rpmi 8226 ◽  
Human Myeloma Cell

Abstract While multiple myeloma (MM) remains incurable presently, expanded therapeutic options over the past decade have improved patient survival markedly. Proteasome inhibitors have redefined the treatment paradigm for myeloma, often serving as the backbone of front-line treatment. Histone deacetylase (HDAC) inhibitors (HDI), although only marginally active as single agent therapy in hematological malignancies, have demonstrated an ability to salvage bortezomib responsiveness in refractory patients, prompting heightened interest in this class of targeted therapeutics in myeloma. HDAC’s represent a family of enzymes, currently with 11 known members in the classical HDAC family, and subdivided into 4 sub-classes. HDAC11 is currently the only member of the sub-class IV and, as the newest member of the HDAC family, its impact on B cell lymphopoiesis and myeloma development is only starting to be unveiled. Intriguingly, we show that mice with germ-line silencing of HDAC11 (HDAC11KO mice) exhibit a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Consistent with this, Tg-HDAC11-eGFP mice, a transgenic strain engineered to express GFP under control of the HDAC11 promoter (Heinz, N Nat. Rev. Neuroscience 2001) reveals that HDAC11 expression is increased in the plasma cell population and to a lesser extent B1 B cells, as compared to earlier lineage stages. Similar observations based on measurements of HDAC11 mRNA were seen in normal human plasma cells. Significant increases in HDAC11 mRNA expression were observed in 7 of 11 primary human multiple myeloma samples and 11 of 12 human myeloma cell lines as compared to normal plasma cells, further emphasizing the potential relevance of HDAC11 to the underlying pathologic processes driving myeloma development and/or survival. Targeted silencing of HDAC11 in RPMI-8226 cells lines using siRNA results in a modest decrease in cell viability as measured by Annexin/PI staining and detection of activated caspase-3. Quisinostat, a second generation pan-HDI, has previously demonstrated activity against human myeloma cell lines in vitro (Stuhmer, Brit J Haematol, 2010), and suppressed bone destruction in an in vivo murine myeloma model (Deleu, Cancer Res, 2009). We similarly observe dose-dependent survival impairment in 10 human myeloma cell lines when cultured in the presence of quisinostat, with EC50’s consistently in the 1-10nM range. Importantly, quisinostat acts synergistically with proteasome inhibitiors (bortezomib and carfilzomib) in RPMI-8226 cells; more importantly, the degree of synergism is amplified in the RPMI-6226-B25 bortezomib-resistant cell line. Although a clear mechanism of action remains to be elucidated, preliminary data suggests that RPMI-8226 cells exposed to quisinostat appear to exhibit a decrease nuclear, but not cytosolic HDAC11. Collectively, these data illustrate a previously unknown role for HDAC11 in plasma cell differentiation and survival. Increased HDAC11 expression seen in myeloma patient specimens and primary myeloma cell lines highlights the potential of HDAC11 as a therapeutic target. Furthermore, we show that quisinostat, a pan-HDI with selectivity towards HDAC11 at lower dosing, acts synergistically with proteasome inhibitors in vitro in proteasome inhibitor sensitive and resistant cell lines. Future work will focus on further elucidating the role of HDAC11 in myeloma survival and drug response, with particular emphasis on proteasome inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival

Leukemia ◽  
2017 ◽  
Vol 31 (12) ◽  
pp. 2661-2669 ◽  
Author(s):  
H Ohguchi ◽  
T Harada ◽  
M Sagawa ◽  
S Kikuchi ◽  
Y-T Tai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Mapk Pathway ◽  
Myeloma Cell ◽  
Growth And Survival ◽  
Multiple Myeloma Cell ◽  
Cell Growth And Survival

scholarly journals Phenotypic analysis of human myeloma cell lines

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 566-572
Author(s):  
C Duperray ◽  
B Klein ◽  
BG Durie ◽  
X Zhang ◽  
M Jourdan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Light Chains ◽  
Cell Phenotype ◽  
Phenotypic Analysis ◽  
Barr Virus ◽  
Human Myeloma Cell

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation, primarily in bone marrow, of a clone of plasma cells. The nature of the stem cells feeding the tumoral compartment is still unknown. To investigate this special point, we have studied the phenotypes of nine well-known human myeloma cell lines (HMCLs) and compared them with those of normal lymphoblastoid cell lines (LCLs). Twenty-four clusters of differentiation involved in B lymphopoiesis were investigated using a panel of 65 monoclonal antibodies (MoAbs). For each cluster, the percentage of positive cells and the antigen density were determined, giving rise to a “quantitative phenotype”. We thus classified the HMCLs into two different groups: those with cytoplasmic mu chains (c mu+) and those without (c mu-). In the first (c mu+) group, comprising seven cell lines, the HMCLs had a phenotype of pre-B/B cells close to that of Burkitt's lymphoma cell lines. They expressed low densities of surface mu chains, without detectable cytoplasmic or surface light chains. Three of them were infected with the Epstein Barr virus (EBV). These c mu+ HMCLs bore most of the B-cell antigens except CD23. They expressed the CALLA antigen (CD10) and lacked the plasma-cell antigen PCA1. In contrast, LCLs expressed surface light chains, high densities of CD23, low densities of PCA1 antigen, and no CD10 antigen. The c mu- HMCLs had a plasma-cell phenotype, lacking most of the B-cell antigens and expressing high densities of PCA1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti–IL-6 antibody-induced apoptosis

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1829-1837 ◽  
Author(s):  
Karène Mahtouk ◽  
Michel Jourdan ◽  
John De Vos ◽  
Catherine Hertogh ◽  
Geneviève Fiol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Lines ◽  
Stromal Cells ◽  
Egf Receptor ◽  
Myeloma Cell ◽  
Factor Activity ◽  
Myeloma Cells ◽  
Induced Apoptosis

Abstract We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor–like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti–IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.

scholarly journals Pixantrone demonstrates significant in vitro activity against multiple myeloma and plasma cell leukemia

2019 ◽  
Vol 98 (11) ◽  
pp. 2569-2578
Author(s):  
Ella Willenbacher ◽  
Karin Jöhrer ◽  
Wolfgang Willenbacher ◽  
Brigitte Flögel ◽  
Richard Greil ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Myeloma Cell ◽  
Plasma Cell Leukemia ◽  
Phase Iii ◽  
In Vivo Model ◽  
Cell Leukemia ◽  
Cam Assay

Abstract Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin’s lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).

scholarly journals Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2219-2227 ◽  
Author(s):  
M Urashima ◽  
A Ogata ◽  
D Chauhan ◽  
MB Vidriales ◽  
G Teoh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
Cell Growth ◽  
Tumor Cell ◽  
Cell Lines ◽  
Interleukin 6 ◽  
Growth Arrest ◽  
Retinoblastoma Protein ◽  
Myeloma Cell ◽  
Phosphorylated Form

Interleukin-6 (IL-6) mediates autocrine and paracrine growth of multiple myeloma (MM) cells and inhibits tumor cell apoptosis. Abnormalities of retinoblastoma protein (pRB) and mutations of RB gene have been reported in up to 70% of MM patients and 80% of MM-derived cell lines. Because dephosphorylated (activated) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated (inactivated) pRB releases this growth arrest, we characterized the role of pRB in IL-6-mediated MM cell growth. Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved MM patient cells and MM-derived cell lines, but pRB was predominantly in its phosphorylated form. In MM cells that proliferated in response to IL-6, exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes. Importantly, culture of MM cells with RB antisense, but not RB sense, oligonucleotide (ODN) triggered IL- 6 secretion and proliferation in MM cells; however, proliferation was only partially inhibited by neutralizing anti-IL-6 monoclonal antibody (MoAb). In contrast to MM cells, normal splenic B cells express dephosphorylated pRB. Although CD40 ligand (CD40L) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells, the addition of exogenous IL-6 to CD40L-treated B cells does not alter either pRB or proliferation, as observed in MM cells. These results suggest that phosphorylated pRB is constitutively expressed in MM cells and that IL-6 further shifts pRB from its dephosphorylated to its phosphorylated form, thereby promoting MM cell growth via two mechanisms; by decreasing the amount of E2F bound by dephosphorylated pRB due to reduced dephosphorylated pRB, thereby releasing growth arrest; and by upregulating IL-6 secretion by MM cells and related IL-6- mediated autocrine tumor cell growth.

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