A systematic classification of death causes in multiple myeloma.
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ABSTRACT:
SUBMITTER: Mai EK
PROVIDER: S-EPMC5843652 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
A systematic classification of death causes in multiple myeloma.
Mai Elias K EK Haas Eva-Maria EM Lücke Stephan S Löpprich Martin M Kunz Christina C Pritsch Maria M Knaup-Gregori Petra P Raab Marc S MS Schlenzka Jana J Bertsch Uta U Hillengass Jens J Goldschmidt Hartmut H
Blood cancer journal 20180308 3
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Project description:PURPOSE. The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM). The recently proposed TC classification grouped MM patients into five classes on the basis of their cyclins D expression profiles and the presence of the main translocations involving the immunoglobulin heavy-chain locus (IGH) at 14q32. In this study, we provide a molecular characterization of the identified TC groups. MATERIALS AND METHODS. The gene expression profiles of purified plasma cells from 50 MM cases were used to stratify the samples into the five TC classes and identify their transcriptional fingerprints. The cyclin D expression data were validated by means of real-time quantitative PCR analysis; fluorescence in-situ hybridization was used to investigate the cyclin D loci arrangements, and to detect the main IGH translocations and the chromosome 13q deletion. RESULTS. Class-prediction analysis identified 112 probe sets as characterizing the TC1, TC2, TC4 and TC5 groups, whereas the TC3 samples showed heterogeneous phenotypes and no marker genes. The TC2 group, which showed extra copies of the CCND1 locus and no IGH translocations or the chromosome 13q deletion, was characterized by the overexpression of genes involved in protein biosynthesis at translational level. A meta-analysis of published datasets validated the identified gene expression signatures. CONCLUSIONS. Our data contribute to the understanding of the molecular and biological features of distinct MM subtypes. The identification of a distinctive gene expression pattern in TC2 patients may improve risk stratification and indicate novel therapeutic targets. Keywords: other
2005-09-01 | GSE2912 | GEO
Project description:To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
| S-EPMC1895543 | biostudies-literature
Project description:BackgroundSteady evolution of therapies has improved prognosis of patients with multiple myeloma (MM) over the past two decades. Yet, knowledge about survival trends and causes of death in MM might play a crucial role in long-term management of this patient collective. Here, we investigate time trends in myeloma-specific survival at the population level over two decades and analyse causes of death in times of prolonged survival.MethodsAge-standardised and age group-specific relative survival (RS) of MM patients aged < 80 years at diagnosis was estimated for consecutive time periods from 2000-2019 using data from the Cancer Registry of North Rhine-Westphalia in Germany. Conditional RS was estimated for patients who already survived one to five years post diagnosis. Causes of death in MM patients were analysed and compared to the general population using standardised mortality ratios (SMR).ResultsThree thousand three hundred thirty-six MM cases were included in the time trend analysis. Over two decades, age-standardised 5-year RS increased from 37 to 62%. Age-specific survival improved from 41% in period 2000-2004 to 69% in period 2015-2019 in the age group 15-69 years, and from 23 to 47% in the age group 70-79 years. Conditional 5-year RS of patients who survived five years after diagnosis slightly improved as compared to unconditional 5-year RS at diagnosis. MM patients are two times more likely to die from non-myeloma malignancies (SMR = 1.97, 95% CI 1.81-2.15) and from cardiovascular diseases (SMR = 2.01, 95% CI 1.86-2.18) than the general population.ConclusionsPrognosis of patients with MM has markedly improved since the year 2000 due to therapeutic advances. Nevertheless, late mortality remains a major concern. As survival improves, second primary malignancies and cardiovascular events deserve increased attention.
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Project description:Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.
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Project description:As a general rule, successful antineoplastic treatments induce an antitumor immune response, even if they were initially designed to target cancer cell-autonomous pathways. In this issue of Blood Cancer Discovery, Gulla and colleagues reveal that the proteasome inhibitor bortezomib induces immunogenic stress and death in multiple myeloma cells, thus explaining its therapeutic efficacy. See related article by Gulla et al., p. 468.
| S-EPMC8513917 | biostudies-literature
Project description:Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.
| S-EPMC7072128 | biostudies-literature
Project description:Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.
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Project description:Multiple Myeloma (MM) is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma and represents approximately 1% of all cancers and 2% of all cancer deaths. MM is a complex disease characterized by numerous genetic alterations and recent mRNA profiling studies have attempted to subclassify the disease to build pathogenetic and prognostic models Correct classification of cancer patients into subtypes is a prerequisite for acute diagnosis and effective treatment. Here we use high accuracy, quantitative proteomics to segregate cancer subtypes directly at the level of expressed proteins. Multiple myeloma is a heterogeneous disease in its initial clinical features as well as its outcome. We investigated two subtypes of Multiple Myeloma: multiple myeloma associated with t(4;14) chromosomal translocation as well as t(4;14)-negative MM subtype. The t(4;14) translocation, found in 15% of multiple myeloma cases, indicates a poor prognosis. Super-SILAC mix was combined of cell lysates from 8 diverse cell lines labelled with heavy amino acids (Lys8 and Arg10). The Super-SILAC library is mixed with samples (lysates), and quantitative mass spectrometric analysis is performed using a setup consisting of LC and on a linear ion trap Orbitrap mass spectrometer with high mass accuracy at the MS and MS/MS levels. This way we have analysed 20 patient samples from present MM. Shotgun proteomic analysis yielded a proteome of more than 5300 quantified proteins overall (3000 on an average per individual sample). High accuracy of quantification allowed robust separation of subtypes by hierarchical clustering on the protein level.
2024-07-15 | PXD003138 | Pride
Project description:Multiple myeloma (MM) remains an incurable malignancy due, in part, to the influence of the bone marrow microenvironment on survival and drug response. Identification of microenvironment-specific survival signaling determinants is critical for the rational design of therapy and elimination of MM. Previously, we have shown that collaborative signaling between β1 integrin-mediated adhesion to fibronectin and interleukin-6 confers a more malignant phenotype via amplification of signal transducer and activator of transcription 3 (STAT3) activation. Further characterization of the events modulated under these conditions with quantitative phosphotyrosine profiling identified 193 differentially phosphorylated peptides. Seventy-seven phosphorylations were upregulated upon adhesion, including PYK2/FAK2, Paxillin, CASL and p130CAS consistent with focal adhesion (FA) formation. We hypothesized that the collaborative signaling between β1 integrin and gp130 (IL-6 beta receptor, IL-6 signal transducer) was mediated by FA formation and proline-rich tyrosine kinase 2 (PYK2) activity. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation under co-stimulatory conditions. Co-culture of MM cells with patient bone marrow stromal cells (BMSC) showed similar β1 integrin-specific enhancement of PYK2 and STAT3 signaling. Molecular and pharmacological targeting of PYK2 specifically induced cell death and reduced clonogenic growth in BMSC-adherent myeloma cell lines, aldehyde dehydrogenase-positive MM cancer stem cells and patient specimens. Finally, PYK2 inhibition similarly attenuated MM progression in vivo. These data identify a novel PYK2-mediated survival pathway in MM cells and MM cancer stem cells within the context of microenvironmental cues, providing preclinical support for the use of the clinical stage FAK/PYK2 inhibitors for treatment of MM, especially in a minimal residual disease setting.
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Project description:Necroptosis is a type of caspase-independent programmed cell death that has been implicated in cancer development. Activation of the canonical necroptotic pathway is often characterized with successive signaling events as the phosphorylation of mixed lineage kinase domain-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3), followed by MLKL oligomerization and plasma membrane rupture. Here, we demonstrate that omega-3 polyunsaturated fatty acids DHA/EPA and the proteasome inhibitor bortezomib induce necroptosis in human multiple myeloma (MM) cells in a RIPK3 independent manner. In addition, it seemed to be that phosphorylation of MLKL was not essential for necroptosis induction in MM cells. We show that treatment of MM cells with these cytotoxic compounds induced cleavage of MLKL into a 35 kDa protein. Furthermore, proteolytic cleavage of MLKL was triggered by activated caspase-3/8/10, and mutation of Asp140Ala in MLKL blocked this cleavage. The pan-caspase inhibitor ZVAD-FMK efficiently prevented DHA/EPA and bortezomib induced cell death. In addition, nuclear translocation of total MLKL and the C-terminus were detected in treated MM cells. Collectively, this present study suggests that caspase-mediated necroptosis may occur under (patho)physiological conditions, delineating a novel regulatory mechanism of necroptosis in RIPK3-deficient cancer cells.
| S-EPMC9369655 | biostudies-literature