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Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinases Is Associated with Multiple Myeloma Progression, Prognosis and Extramedullary Plasmacytoma
Conclusions: Our results suggest that TIMP1, 2 and MMP14, 24 were associated with EMP formation. Among those factors, TIMP1 is the one which may play a key role for MM progression and chemo-resistance based on the results revealing its upregulation by antineoplastic agents and association with poor prognosis of MM patients. Our results is consistent with a previous report describing that high serum TIMP1 concentration was associated with poor prognosis of MM. TIMP is recently shown to play another role besides negative regulator for MMP, so further study to elucidate its specific role for chemo-resistance contributes to de...
Source: Blood - November 21, 2018 Category: Hematology Authors: Ishihara, R., Murakami, Y., Homma, K., Watanabe, S., Oda, T., Sunaga, M., Yamane, E., Kobayashi, N., Osaki, Y., Ishizaki, T., Shimizu, H., Iriuchishima, H., Koiso, H., Tsukamoto, N., Yokohama, A., Nanami, G., Ino, R., Saitoh, T., Murakami, H., Handa, H. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II Source Type: research

Blockade of Ubiquitin Receptor PSMD4/Rpn10 Triggers Cytotoxicity and Overcomes Bortezomib-Resistance in Multiple Myeloma
ConclusionOur preclinical data validates targeting 19S proteasome ubiquitin receptor Rpn10 upstream of the proteasome in the ubiquitin proteasomal cascade, and provides the framework for clinical evaluation of Rpn10 inhibitors to overcome PI resistance and improve patient outcome in MM.DisclosuresAnderson: C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder.
Source: Blood - November 21, 2018 Category: Hematology Authors: Song, Y., Ray, A., Chauhan, D., Anderson, K. Tags: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster II Source Type: research

Chidamide, a Novel Histone Deacetylase Inhibitor, Inhibits Multiple Myeloma Cells Proliferation through Succinate Dehydrogenase Subunit a
Most patients with multiple myeloma (MM) would finally relapse. Current chemotherapy regimens have limited effect on relapse MM patients. As a new histone deacetylase inhibitor, chidamide has been used in malignancy treatment such as peripheral T-cell lymphoma. However, it is still unknown if chidamide can be used in MM.To determine the target gene of chidamide in MM patients, we performed RNA-Seq analysis using 3 MM patients' bone marrow mononuclear cells. Their BMMCs were cultured with 6μM chidamide or not, and six of the most significantly changed coding genes were selected. Realtime RT-PCR showed that compared with ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sun, Y., Liu, P., Li, J. Tags: 653. Myeloma: Therapy, excluding Transplantation: Poster I Source Type: research

Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted
In conclusion, phosphorylation by Aurora Kinase A and ubiquitination by MDM2 contribute to SETD2 non-genomic loss of function in advanced-phase CML. Loss of SETD2/H3K36me3 is associated with increased DNA damage and impaired HR repair. Restoring physiological H3K36me3 levels may help improve the outcome of this critical subset of pts.Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma).Figure 1.DisclosuresCastagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consulta...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., De Santis, S., Monaldi, C., Bavaro, L., Martelli, M., Castagnetti, F., Gugliotta, G., Rosti, G., Fontana, M. C., Dan, E., Sinigaglia, B., Iurlo, A., Orofino, N., Abruzzese, E., Salvucci, M., Pregno, P., Gozzini, A., Crugnola, M., Albano, F., Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research

MDM2 and Aurora Kinase a Contribute to SETD2 Loss of Function in Advanced Systemic Mastocytosis: Implications for Pathogenesis and Treatment
The SETD2 gene encodes the only methyltransferase responsible for histone H3 lysine 36 trimethylation (H3K36Me3) in humans. H3K36me3 play a key role in preserving the fidelity of transcription elongation and splicing. In addition, SETD2/H3K36me3 have more recently been implicated in the maintenance of genomic integrity by regulating homologous recombination (HR) repair, Mismatch Repair (MMR) mitotic spindle assembly and chromosome segregation. SETD2 deletions and/or inactivating mutations occur in many solid tumors and have recently been found also in acute leukemias. We have reported that the HMC-1.1 and -1.2 mast cell le...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., Monaldi, C., De Santis, S., Papayannidis, C., Rondoni, M., Bavaro, L., Martelli, M., Maria Chiara, A., Curti, A., Ficarra, E., Paciello, G., Fontana, M. C., Zanotti, R., Bonifacio, M., Scaffidi, L., Pagano, L., Criscuolo, M., Albano, F., Cice Tags: 635. Myeloproliferative Syndromes: Basic Science: Poster I Source Type: research

Targeting Insulin-like Growth Factor in Multiple Myeloma: Novel Strategies in the Treatment of Proteasome Inhibitor Resistant Cells
Conclusion: The IGF1 signaling pathway is involved in proteasome inhibitor sensitivity and plays a key role in chemokine production of the HUVEC. Our data also suggested that administration of IGF1R inhibitor, linsitinib, might be a powerful strategy against myeloma cells and enhance cytotoxic effects of proteasome inhibitors in those residual MM cells.DisclosuresOhyashiki: MSD,: Honoraria, Research Funding; Bristol Meyer Squibb KK,: Honoraria, Research Funding; Kyowakko Kirin KK,: Research Funding; Celegene KK,: Honoraria, Research Funding; Pfizer KK,: Honoraria, Research Funding; Novartis KK,: Honoraria, Research Funding...
Source: Blood - November 21, 2018 Category: Hematology Authors: Tanaka, Y., Okabe, S., Tauchi, T., Ito, Y., Ohyashiki, K. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases Source Type: research

Overexpressed Melk Promotes the Stability of EZH2 through Phosphorylation in Natural Killer/T Cell Lymphoma (NKTL)
In this study, we examined EZH2 protein turnover mechanisms in the NKTL context.The serine/threonine kinase Melk is one of the overexpressed genes in NKTL patient samples and cell lines, and the interaction between Melk and EZH2 was established by co-immunoprecipitation. Inhibition of Melk using inhibitor or siRNA both resulted in a decrease of EZH2 protein levels in NKTL cells, whereas there was no change in the mRNA level of EZH2, suggesting that Melk regulated EZH2 at the protein level. Next, we observed a change of EZH2 ubiquitination upon manipulation of Melk expression.Next, in order to confirm that Melk truly affect...
Source: Blood - November 21, 2018 Category: Hematology Authors: Li, B., Kappei, D., Yan, J., Eichhorn, P., Ng, S. B., Chng, W. J. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster II Source Type: research