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Survivin suppressant YM155 induces cell death via proteasomal degradation of c-Myc in multiple myeloma cells
Abstracts PO-272
Hematology and Hematologic Malignancies, University of Utah,
Survivin suppressant YM155 induces cell death via proteasomal degradation of c-Myc in multiple myeloma cells
plantation, University Medical Center Hamburg-Eppendorf, Hamburg,
M. Asahi, S. Ito, Y. Ishida Hematology & Oncology, Department of Internal Medicine, Department of Medical Oncology, Iwate Medical University School of Medicine
Introduction: Survivin is a member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. However, the effect of this agent on multiple myeloma (MM) cells remains unclear. Materials & Methods Results: Five human MM cell lines, RPMI8226, U266, KMS20, KMS28PE, and KMS34 were used. Cell proliferation and cell death were evaluated by MTT assay and by flow cytometric analysis with annexin V/PI staining. Protein expressions were analyzed with immunoblot. For proteasome inhibitory assay, cells were treated with YM155 and/or MG132 for 6 hours. Results: YM155 inhibited cell proliferation of these cells in a dose-dependent manner. Annexin V assay showed that YM155 induced apoptosis in these cells. To better understand these effects of YM155 on MM cells, we evaluated the intracellular signaling and apoptosis-associated protein status. Immunoblot analyses showed that YM155 reduced not only survivin but also Mcl-1 and XIAP expressions. We also observed the activation of caspase-3 and PARP in YM155-treated cells, indicating that YM155 induces caspasedependent apoptosis. In contrast, YM155 did not affect phosphorylation status of Erk1/2 and STAT3. Interestingly, YM155 suppressed c-Myc and IRF4 expressions, both of which are recognized as an important oncogene in the pathogenesis of MM. In addition, qPCR assay showed that YM155 treatment did not reduce c-Myc mRNA level. On the other hand, proteasome inhibitor prevented the suppression of c-Myc expression by YM155 treatment, indicating a proteasomal degradation of c-Myc by YM155. Conclusion: YM155 suppresses cell proliferation and survival in MM cells in part via not only inhibiting anti-apoptotic proteins such as survivin, Mcl-1 and XIAP but also suppressing c-Myc oncogene. Further study is needed to clarify the molecular mechanism of c-Myc degradation induced by YM155. Our results may provide a new concept in c-Myc-targeting therapy for MM.
Huntsman Cancer Institute, Salt Lake City, UT; Stem Cell TransGermany; Flow Cytometry Core Facility, University of Utah Health Sciences Center, Salt Lake City, UT; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine IV, University Hospital RWTH Aachen, Aachen, Germany; ARUP Laboratories, Hematopathology University of Utah, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UT
Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients’ bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy-resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at two different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients’ BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients’ BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients.
PO-274 The chemokine CXCL9 (MIG) is an independent predictor of overall survival in newly diagnosed multiple myeloma
PO-273
A. Bolomsky, M. Schreder, N. Zojer, H. Ludwig
CD229 is expressed on the surface of plasma cells carrying an aberrant phenotype and chemotherapy-resistant precursor cells in Multiple Myeloma
Wilhelminen Cancer Research Institute, Department of Medicine I,
S. Yousef, M. Kovacsovics-Bankowski, M.E. Salama, N. Bhardwaj, M. Steinbach, A. Langemo, T. Kovacsovics, J. Marvin, M. Binder, J. Panse, N. Kröger, T. Luetkens, D. Atanackovic
Wilhelminenhospital, Vienna, Austria
Background: The CXCR3 binding molecules CXCL9-11 have been associated with tumor progression, immune escape and angiogenesis in several malignancies. Information about the precise role of CXCR3 binding chemokines in MM is limited. We here aimed to evaluate the prognostic relevance of CXCL9 in MM.
15th International Myeloma Workshop, September 23-26, 2015
- e237
Hematology and Hematologic Malignancies, University of Utah,
Survivin suppressant YM155 induces cell death via proteasomal degradation of c-Myc in multiple myeloma cells
plantation, University Medical Center Hamburg-Eppendorf, Hamburg,
M. Asahi, S. Ito, Y. Ishida Hematology & Oncology, Department of Internal Medicine, Department of Medical Oncology, Iwate Medical University School of Medicine
Introduction: Survivin is a member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. However, the effect of this agent on multiple myeloma (MM) cells remains unclear. Materials & Methods Results: Five human MM cell lines, RPMI8226, U266, KMS20, KMS28PE, and KMS34 were used. Cell proliferation and cell death were evaluated by MTT assay and by flow cytometric analysis with annexin V/PI staining. Protein expressions were analyzed with immunoblot. For proteasome inhibitory assay, cells were treated with YM155 and/or MG132 for 6 hours. Results: YM155 inhibited cell proliferation of these cells in a dose-dependent manner. Annexin V assay showed that YM155 induced apoptosis in these cells. To better understand these effects of YM155 on MM cells, we evaluated the intracellular signaling and apoptosis-associated protein status. Immunoblot analyses showed that YM155 reduced not only survivin but also Mcl-1 and XIAP expressions. We also observed the activation of caspase-3 and PARP in YM155-treated cells, indicating that YM155 induces caspasedependent apoptosis. In contrast, YM155 did not affect phosphorylation status of Erk1/2 and STAT3. Interestingly, YM155 suppressed c-Myc and IRF4 expressions, both of which are recognized as an important oncogene in the pathogenesis of MM. In addition, qPCR assay showed that YM155 treatment did not reduce c-Myc mRNA level. On the other hand, proteasome inhibitor prevented the suppression of c-Myc expression by YM155 treatment, indicating a proteasomal degradation of c-Myc by YM155. Conclusion: YM155 suppresses cell proliferation and survival in MM cells in part via not only inhibiting anti-apoptotic proteins such as survivin, Mcl-1 and XIAP but also suppressing c-Myc oncogene. Further study is needed to clarify the molecular mechanism of c-Myc degradation induced by YM155. Our results may provide a new concept in c-Myc-targeting therapy for MM.
Huntsman Cancer Institute, Salt Lake City, UT; Stem Cell TransGermany; Flow Cytometry Core Facility, University of Utah Health Sciences Center, Salt Lake City, UT; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine IV, University Hospital RWTH Aachen, Aachen, Germany; ARUP Laboratories, Hematopathology University of Utah, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UT
Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients’ bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy-resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at two different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients’ BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients’ BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients.
PO-274 The chemokine CXCL9 (MIG) is an independent predictor of overall survival in newly diagnosed multiple myeloma
PO-273
A. Bolomsky, M. Schreder, N. Zojer, H. Ludwig
CD229 is expressed on the surface of plasma cells carrying an aberrant phenotype and chemotherapy-resistant precursor cells in Multiple Myeloma
Wilhelminen Cancer Research Institute, Department of Medicine I,
S. Yousef, M. Kovacsovics-Bankowski, M.E. Salama, N. Bhardwaj, M. Steinbach, A. Langemo, T. Kovacsovics, J. Marvin, M. Binder, J. Panse, N. Kröger, T. Luetkens, D. Atanackovic
Wilhelminenhospital, Vienna, Austria
Background: The CXCR3 binding molecules CXCL9-11 have been associated with tumor progression, immune escape and angiogenesis in several malignancies. Information about the precise role of CXCR3 binding chemokines in MM is limited. We here aimed to evaluate the prognostic relevance of CXCL9 in MM.
15th International Myeloma Workshop, September 23-26, 2015
- e237