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ABSTRACT: ABSTRACT Lenalidomide (LEN) treatment in multiple myeloma (MM) results in superior outcome. However, there is concern for increased myelodysplastic syndromes/acute myeloid leukemias (MDS/AML) associated with LEN. Thus, bone marrow morphology and cytogenetic studies from 40 patients were evaluated for early signs of MDS prior to therapy, during therapy and at follow-up. Newly diagnosed MM patients treated with LEN and dexamethasone (LD) alone or followed by ASCT (LD/ASCT), or relapsed/refractory MM patients treated with LEN, bendamustine and dexamethasone (BLD) were included. One patient developed MDS. Baseline prevalence of mild morphologic myelodysplasia was highest in pretreated MM patients (BLD, 71%), but was also seen in newly diagnosed patients (LD and LD/ASCT, 17%). Prevalence of myelodysplasia did not increase over time. Thus, this study did not reveal rapidly emerging MDS in 39 of 40 MM patients treated with LEN. Development of MDS in one patient suggests that longer follow up is needed for all. Trials were registered at www.clinicaltrials.gov as #NCT00777881 and #NCT01042704.
Leukemia & lymphoma 12/2012; · 2.40 Impact Factor
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Annals of Hematology 04/2012; 88(10):1043-1044. · 2.62 Impact Factor
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ABSTRACT: BM stromal cells (BMSCs) are key players in the microenvironmental support of multiple myeloma (MM) cell growth and bone destruction. A spliced form of the X-box-binding protein-1 (XBP1s), a major proximal effector of unfolded protein response signaling, is highly expressed in MM cells and plays an indispensable role in MM pathogenesis. In the present study, we found that XBP1s is induced in the BMSCs of the MM microenvironment. XBP1s overexpression in healthy human BMSCs enhanced gene and/or protein expression of VCAM-1, IL-6, and receptor activator of NF-κB ligand (RANKL), enhancing BMSC support of MM cell growth and osteoclast formation in vitro and in vivo. Conversely, deficiency of XBP1 in healthy donor BMSCs displayed a range of effects on BMSCs that were opposite to those cells with overexpression of XBP1s. Knock-down of XBP1 in MM patient BMSCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNFα and reversed their enhanced support of MM-cell growth and osteoclast formation. Our results demonstrate that XBP1s is a pathogenic factor underlying BMSC support of MM cell growth and osteoclast formation and therefore represents a therapeutic target for MM bone disease.
Blood 03/2012; 119(18):4205-14. · 9.90 Impact Factor
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ABSTRACT: We identified nocodazole as a potent antimyeloma drug from a drug screening library provided by the Multiple Myeloma Research Foundation. Nocodazole is a benzimidazole that was originally categorized as a broad-spectrum anthelmintic drug with antineoplastic properties. We found that nocodazole inhibited growth and induced apoptosis of primary and multiresistant multiple myeloma cells cultured alone and in the presence of bone marrow stromal cells. Nocodazole caused cell-cycle prophase and prometaphase arrest accompanied by microtubular network disarray. Signaling studies indicated that increased expression of Bim protein and reduced X-linked inhibitor of apoptosis protein and Mcl-1(L) levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, triggered by the activation of c-jun-NH(2) kinase (JNK) instead of p38 kinase or extracellular signal-regulated kinases. Treatment with JNK inhibitor decreased Bcl-2 phosphorylation and subsequently reduced nocodazole-induced cell death. Nocodazole combined with dexamethasone significantly inhibited myeloma tumor growth and prolonged survival in a human xenograft mouse model. Our studies show that nocodazole has potent antimyeloma activity and that targeting the microtubular network might be a promising new treatment approach for multiple myeloma.
Molecular Cancer Therapeutics 08/2011; 10(10):1886-96. · 5.23 Impact Factor
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ABSTRACT: STAT1 is the main signal transducer for type I and II IFNs and plays a central role in the regulation of innate and adaptive immune responses. We used Stat1-deficient mice to test the role of donor Stat1 in MHC-matched minor histocompatibility antigen-mismatched (mHA-mismatched) and fully MHC-mismatched models of bone marrow transplantation. Lack of Stat1 in donor splenocytes reduced graft-versus-host disease (GVHD) in both immunogenetic disparities, leading to substantially attenuated morbidity and mortality. Donor Stat1 deficiency resulted in reduced alloantigen-induced activation and expansion of donor T cells and correlated with the expansion of CD4+CD25+Foxp3+ Tregs in vivo. This expansion of Tregs was further confirmed by studies showing that Stat1 deficiency promoted the proliferation, while inhibiting the apoptosis, of natural Tregs, and that absence of Stat1 enhanced the induction of inducible Tregs both in vitro and in vivo. Ex vivo expanded Stat1-/- Tregs were superior to wild-type Tregs in suppressing alloantigen-driven expansion of T cells in vitro and in inhibiting the development of GVHD. These observations demonstrate that Stat1 is a regulator of Tregs and that targeting Stat1 in CD4+ T cells may facilitate in vitro and in vivo expansion of Tregs for therapeutic use.
The Journal of clinical investigation 06/2011; 121(7):2554-69. · 15.39 Impact Factor
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ABSTRACT: Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, ∼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.
International Immunology 06/2011; 23(6):375-84. · 3.41 Impact Factor
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ABSTRACT: Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide, are highly active in multiple myeloma (MM) treatment. However, the precise mechanisms of action and resistance in MM are unresolved. Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding protein-β (C/EBPβ) resulting in abrogation of cell proliferation. Overexpression of C/EBPβ rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPβ is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPβ protein led to impaired transcription of interferon regulatory factor 4 (IRF4). Down-regulation of IRF4 by lenalidomide was confirmed by longitudinal studies of bone marrow samples from 23 patients obtained before and during lenalidomide treatment using CD138⁺/IRF4⁺ double labeling. In contrast to down-regulation of C/EBPβ protein, IMiD compounds did not alter C/EBPβ mRNA levels or protein stability, suggesting translational regulation of C/EBPβ. We could demonstrate that C/EBPβ protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPβ axis by IMiD compounds was not observed in IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target to overcome drug resistance.
Blood 03/2011; 117(19):5157-65. · 9.90 Impact Factor
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ABSTRACT: The aim of this study was to delineate the temporal and spatial sequence of STAT1 and STAT3 activation during development of GVHD following fully Major Histocompatibility Complex (MHC)-mismatched allogeneic Bone Marrow Transplantation (BMT). Activation of inflammatory signaling pathways in GVHD target organs was assessed by western blotting, phospho-flow cytometry and electromobility shift assays (EMSA). Development of GVHD was associated with significant expansion of phospho[p]-STAT1 and p-STAT3 expressing CD4(+) T cells and CD8(+) T cells. GVHD-specific STAT3/STAT1 activation preceded activation of Nuclear Factor-κB (NF-κB) and Mitogen Activated Protein Kinase (MAPK) and was associated with subsequent induction of STAT1 or STAT3-dependent inflammatory gene-expression programs (e.g. expression of IRF-1, SOCS1, IL-17). Our studies may help to establish a functional hierarchy of the signaling events leading to the development of GVHD and could be helpful in designing new molecularly targeted treatment approaches for GVHD.
Cellular Immunology 02/2011; 268(1):37-46. · 1.97 Impact Factor
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ABSTRACT: Immunomodulatory derivatives of thalidomide (IMiDs) have been used for the treatment of myelodysplastic syndrome and multiple myeloma; however, the mechanism of action of IMiDs is largely unknown. The purpose of this review is to provide an overview of recent findings on the mechanism of action of IMiDs, its use as a new treatment modality for various hematologic malignancies, and problems associated with stem cell mobilization after lenalidomide treatment.
Recent clinical trials revealed lenalidomide as a promising new agent for the treatment of follicular non-Hodgkin's lymphoma (NHL) and also diffuse large B-cell lymphoma. Pomalidomide was shown to be even more effective in refractory multiple myeloma than lenalidomide. New guidelines for the management of venous thromboembolism have been established. The chemokine receptor 4 (CXCR4) inhibitor, AMD-3100, is recommended for patients who have received lenalidomide and failed to mobilize stem cells after G-SCF and cyclophosphamide. Preclinical studies investigated the pleiotropic functions of IMiDs, with a particular focus on immune modulation, their effects on new targets, stem cells and disruption of plasma cell microenvironment interactions.
More and more indications for the use of IMiDs in hematologic malignancies have been identified. In order to establish better clinical usage of IMiDs, it is of utmost importance to clarify the antitumor mechanism of IMiDs. Here, we provide a review on the recent advances in the development of IMiDs. New guidelines for venous thromboembolism prophylaxis and stem cell mobilization failure associated with lenalidomide treatment have been established.
Current opinion in oncology 11/2010; 22(6):579-85. · 4.09 Impact Factor
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ABSTRACT: We used a novel high-throughput drug screening assay, based on Luminex technology, to identify anti-myeloma agents capable of inhibiting cytokines and growth factors essential for multiple myeloma (MM) from a chemical library of 1120 compounds provided by MMRF. Tetracycline derivatives inhibited MM cell proliferation and osteoclast activating factors without obvious effect on cell viability. Steroid compounds specifically decreased angiogenesis-related factors, but stimulated osteoclast activating factors. Antihelmintic drugs potently inhibited cytokines and were cytotoxic. The screen identified potential candidates with potent anti-MM properties that need further investigation.
Leukemia research 07/2010; 34(7):917-24. · 2.36 Impact Factor
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ABSTRACT: We report a case of a female with stage I infiltrating ductal carcinoma who received adjuvant therapy including trastuzumab. One year later she developed lytic lesions and was retreated with trastuzumab that was held after she developed symptomatic heart failure. Lytic lesions were attributed to relapse of breast cancer, and cardiac failure attributed to prior trastuzumab therapy. After complications necessitated multiple hospitalizations, a further workup revealed that the lytic lesions were not metastatic breast cancer but multiple myeloma. Her advanced multiple myeloma was associated with systemic amyloidosis involving gut and heart, which ultimately led to her demise. This report addresses the pitfalls of overlapping symptoms and the question of which patients with suspected metastatic disease should undergo a biopsy.
Journal of Oncology 01/2010; 2010:509530.
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ABSTRACT: The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.
Blood 11/2009; 115(3):605-14. · 9.90 Impact Factor
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Rekha Pal,
Martin Janz,
Deborah L Galson,
Margarete Gries,
Shirong Li,
Korinna Jöhrens,
Ioannis Anagnostopoulos,
Bernd Dörken,
Markus Y Mapara,
Lisa Borghesi,
Lela Kardava,
G David Roodman,
Christine Milcarek, Suzanne Lentzsch
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ABSTRACT: CCAAT/enhancer-binding protein beta (C/EBPbeta), also known as nuclear factor-interleukin-6 (NF-IL6), is a transcription factor that plays an important role in the regulation of growth and differentiation of myeloid and lymphoid cells. Mice deficient in C/EBPbeta show impaired generation of B lymphocytes. We show that C/EBPbeta regulates transcription factors critical for proliferation and survival in multiple myeloma. Multiple myeloma cell lines and primary multiple myeloma cells strongly expressed C/EBPbeta, whereas normal B cells and plasma cells had little or no detectable levels of C/EBPbeta. Silencing of C/EBPbeta led to down-regulation of transcription factors such as IRF4, XBP1, and BLIMP1 accompanied by a strong inhibition of proliferation. Further, silencing of C/EBPbeta led to a complete down-regulation of antiapoptotic B-cell lymphoma 2 (BCL2) expression. In chromatin immunoprecipitation assays, C/EBPbeta directly bound to the promoter region of IRF4, BLIMP1, and BCL2. Our data indicate that C/EBPbeta is involved in the regulatory network of transcription factors that are critical for plasma cell differentiation and survival. Targeting C/EBPbeta may provide a novel therapeutic strategy in the treatment of multiple myeloma.
Blood 09/2009; 114(18):3890-8. · 9.90 Impact Factor
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ABSTRACT: Monoclonal proteins (paraproteins) may be detected in the sera in approximately 1% of the general population and are frequently associated with peripheral neuropathy. Paraproteinemic neuropathy (PPN) is most commonly associated with monoclonal gammopathy of undetermined significance, and may also occur in the context of multiple myeloma, amyloidosis, cryoglobulinemia, and other hematologic malignant and nonmalignant conditions. Possible malignant conversion of underlying benign monoclonal gammopathy should be closely monitored, and risk factors include progression of neuropathy and rising titers of monoclonal protein. PPN is frequently associated with autoantibodies targeting peripheral nerve antigens, including anti-MAG and anti-GM1 antibodies. Therapy is mostly based on the treatment of the underlying hematologic disorder. Risks and benefits should be carefully evaluated as treatment may be associated with considerable morbidity. Rituximab may be helpful in treatment of IgM-PPN, and paraproteinemic multifocal motor neuropathy usually responds to IVIG. Plasmapheresis is more effective with IgG/IgA paraproteinemic neuropathies. At this time it is not clear whether mere presence of neuropathy warrants more aggressive treatment of otherwise quiescent hematologic malignances (e.g. smoldering myeloma).
Leukemia & lymphoma 08/2009; 50(9):1422-33. · 2.40 Impact Factor
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Shaji Kumar,
Sergio Giralt,
Edward A Stadtmauer,
Jean L Harousseau,
Antonio Palumbo,
William Bensinger,
Raymond L Comenzo, Suzanne Lentzsch,
Nikhil Munshi,
Ruben Niesvizky, [......],
Kenneth C Anderson,
Patrizia Tosi,
Pieter Sonneveld,
Orhan Sezer,
David Vesole,
Michele Cavo,
Hermann Einsele,
Paul G Richardson,
Brian G M Durie,
S Vincent Rajkumar
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ABSTRACT: The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.
Blood 07/2009; 114(9):1729-35. · 9.90 Impact Factor
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Annals of Hematology 04/2009; 88(10):1043-4. · 2.62 Impact Factor
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ABSTRACT: Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.
Molecular Cancer Therapeutics 07/2008; 7(6):1494-505. · 5.23 Impact Factor
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ABSTRACT: Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. The multiple myeloma-induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions. Recently the biologic mechanism involved in the imbalance between osteoclast activation and osteoblast inhibition induced by multiple myeloma cells has begun to be clarified. In this article, the pathophysiology underlying the imbalanced bone remodeling and potential new strategies for the treatment of bone disease in multiple myeloma are reviewed.
Hematology/Oncology Clinics of North America 01/2008; 21(6):1035-49, viii. · 2.64 Impact Factor
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ABSTRACT: Clinical trials have shown the high anti-myeloma activity of the proteasome inhibitor bortezomib. The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma (MM) and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138(+) myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose-dependent activation of caspases-3, -8 and -9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species (ROS) generation that was accompanied by p53, H2A.X and p38-mitogen-activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N-acetyl-L-cysteine. The combination of bortezomib and PXD101 also resulted in synergistic inhibition of osteoclast formation. In conclusion, bortezomib and PXD101 have different molecular targets. The combination induces cell death in myeloma cells via ROS-mediated DNA damage and also inhibits osteoclastogenesis. Therefore, this study provides the rationale for the clinical evaluation of bortezomib combined with PXD101 in patients with MM.
British Journal of Haematology 12/2007; 139(3):385-97. · 4.94 Impact Factor
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ABSTRACT: Non-steroidal anti-inflammatory drugs have been shown to inhibit carcinogenesis in colon cancer, and to induce apoptosis in a variety of tumor cell lines. Some anti-tumor effects are thought to be related to their cyclooxygenase-2-inhibitory activity, but recent studies have shown that non-steroidal anti-inflammatory drugs exert their anti-tumor effect via cyclooxygenase-2-independent mechanism. SDX-308 (CEP-18082) is a non-cyclooxygenase-2-inhibiting indole-pyran analog and is structurally related to SDX-101, an R-enantiomer of etodolac. SDX-308 has a potent anti-myeloma effect and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia. In addition SDX-308 inhibits osteoclast formation and activity and thereby might be an attractive drug for the treatment of diseases with increased osteoclast activity such as osteolytic lesions in multiple myeloma and metastatic carcinomas, as well as osteoporosis. This review covers future application of SDX-308 as an anti-myeloma drug regulating increased osteoclast activity.
Archiv der Pharmazie 11/2007; 340(10):511-6. · 1.71 Impact Factor
