Multiple Myeloma Exemplifies a Model of Cancer Based on Tissue Disruption as the Initiator Event

The standard model of multiple myeloma (MM) oncogenesis is based on the genetic instability of MM cells and presents its evolution as the emergence of clones with more and more aggressive genotypes, giving them surviving and proliferating advantage. The micro-environment has a passive role. In contrast, many works have shown that the progression of MM is also characterized by the selection of clones with extended phenotypes able to destroy bone trabeculae, suggesting a major role for early micro-environmental disruption. We present a model of MM oncogenesis in which genetic instability is the consequence of the disruption of normal interactions between plasma cells and their environment, the bone remodeling compartment. These interactions, which normally ensure the stability of the genotypes and phenotypes of normal plasma cells could be disrupted by many factors as soon as the early steps of the disease (MGUS, pre-MGUS states). Therapeutical implications of the model are presented

Detection of t(11;14) using interphase molecular cytogenetics in mantle cell lymphoma and atypical chronic lymphocytic leukemia

The chromosomal translocation t(11;14)(q13;q32) fuses the IGH and CCND1 genes and leads to cyclin D1 overexpression. This genetic abnormality is the hallmark of mantle cell lymphoma (MCL), but is also found in some cases of atypical chronic lymphocytic leukemia (CLL), characterized by a poor outcome. For an unequivocal assessment of this specific chromosomal rearrangement on interphase cells, we developed a set of probes for fluorescence in situ hybridization (FISH). Northern blotting was performed for analysis of the cyclin D1 expression in 18 patients. Thirty-eight patients, with either a typical MCL leukemic phase (17 patients) or atypical CLL with an MCL-type immunophenotype, i.e., CD19+, CD5+, CD23(-/low), CD79b/sIgM(D)++, and FMC7+ (21 patients), were analyzed by dual-color interphase FISH. We selected an IGH-specific BAC probe (covering the JH and first constant regions) and a commercially available CCND1 probe. An IGH-CCND1 fusion was detected in 28 of the 38 patients (17 typical MCL and 11 cases with CLL). Cyclin D1 was not overexpressed in two patients with typical MCL and an IGH- CCND1 fusion. In view of the poor prognosis associated with MCL and t(11;14)- positive CLL, we conclude that this set of probes is a valuable and reliable tool for a rapid diagnosis of these entities

Le rôle du complexe Mcl-1/Bim dans la régulation de l'apoptose des cellules de myélome multiple

Le myélome multiple est une tumeur plasmocytaire maligne. L'IL-6 est essentielle pour la survie de ces cellules, elle régule positivement une protéine anti-apoptotique primordiale: Mcl-1. La protéine pro-apoptotique Bim a été décrite par son interaction avec Mcl-1 et est impliquée dans l'initiation de l'apoptose. Nous montrons que les trois isoformes de Bim sont exprimées dans les cellules de myélome comme dans les lymphocytes B. Elles sont localisées à la mitochondrie, associées à Mcl-1 et Bcl-2 qui la neutraliseraient. Il n'y a pas de Bim libre. La privation en IL-6 induit l'apoptose associée à l'augmentation de Bim et à la diminution de Mcl-1. Dans les cellules apoptotiques, Bim reste lié à Bcl-2 alors qu'il est libéré de Mcl-1 pour activer Bax. Mcl-1L et BimEL sont clivées par les caspases générant des formes pro-apoptotiques qui amplifient l'apopotose. Ainsi le complexe Bim/Mcl-1 est essentiel dans la régulation de l'apoptose des ces cellules.Multiple myeloma is a plasma cell malignancy. IL-6 is essential for survival of myeloma cells, it up-regulates Mcl-1. Mcl-1 has a major role in myeloma cell survival. The pro-apoptotic protein Bim has an important role as an initiator of apoptosis. We show that the three Bim isoforms are expressed on myeloma cells as well as on B cells. They are endogenously associated to Mcl-1 and Bcl-2. Bim is preferentially co-localised in mitochondria along with the anti-apoptotic counterparts. They neutralise Bim since there is no free Bim. IL-6 starvation induces apoptosis associated to the simultaneous Bim up-regulation and Mcl-1 diminution. Upon apoptosis induction Bim/Bcl-2 complex is not modified whereas Bim/Mcl-1 complex is nearly abolished leading to Bim release and to Bax activation. Mcl-1L and BimEL are cleaved by caspases giving rise to pro-apototic fragments that contribute to the apoptosis amplification loop. Indeed, Bim/Mcl-1 complex is essential for apoptosis regulation of those cells.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory

The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided

Effets in vitro des bisphosphonates sur la tumeur et son environnement dans le myélome multiple. Implication des protéines anti-apoptotiques de la famille BCL-2 dans le myélome multiple

Le myélome multiple (MM) est une lymphopathie B maligne caractérisée par l'expansion clonale de plasmocytes tumoraux qui s'accumulent dans la moelle osseuse. L'IL-6 est le facteur de survie majeur des plasmocytes de MM. Les bisphosphonates peuvent réduire les lésions ostéolytiques et ainsi améliorer la qualité de vie des patients atteints de MM. Nous avons étudié l'effet du zolédronate, un puissant bisphosphonate, in vitro dans le MM. Nous avons démontré (1) qu'il induisait l'apoptose dans les plasmocytes malins et les cellules stromales de l'environnement tumoral, (2) qu'il diminue de la sécrétion d'IL-6 et de MMP-1 par les cellules stromales, (3) qu'il est capable d'augmenter la production de MMP-2 par les cellules stromales.....Nous avons montré que l'inhibition de Mcl-1 induit une apoptose intense et rapide. L'inhibition de Bcl.-2 sensibilise les cellules à l'apoptose médiée par la dexaméthasone tandis que l'inhibition de Bcl-XL n'entraîne pas d'apoptose dans les conditions testées. Ainsi, nous avons démontré que Mcl-1 est la protéine essentielle de survie des cellules humaines de MM.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Immunité innée des patients infectés par le virus de l'immunodéficience humaine et atteints de lymphome

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

A bone paradigm challenging the standard model of myeloma oncogenesis

International audienceThe standard model of multiple myeloma (MM) oncogenesis from monoclonal gammopathy of undetermined significance (MGUS) relies on genetic instability in the normal counterparts of MM cells. However, the impor-tance of both MGUS-associated and MM-induced bone changes has been recently re-appraised, emphasizing the bone microenvironment (BME) as a tissue of significance. In this review, we propose that early BME alterations (bone senescence and inflammation, i.e., bone inflamm'aging) at the pre-MGUS stage could be causal, and not simply permissive, and creative of phenotypic instability and genetic alterations thanks to the concept of tissue disruption-induced cell stochasticity (TiDiS). This article offers a bone scenario challenging the chromosome-and-gene-centric standard model of MM oncogenesis. The high incidence of both MGUS and MM in Gaucher disease supports such a scenario

Expression de la protéine anti-apoptotitque MCL-1 dans le myélome multiple (corrélation avec l'activité de la maladie)

Le myélome multiple (MM) est une hémopathie maligne caractérisée par l'expansion clonale de plasmocytes tumoraux qui s'accumulent dans la moelle osseuse. La protéine anti-apoptotique Mcl-1 est un facteur de survie des plasmocytes de MM. Nous avons quantifié en cytométrie en flux, par quadruple marquage, l'expression de Mcl-1 chez 45 patients atteints de MM. Nous avons étudié en parallèle à Mcl-1, l'expression de la protéine Bcl-2, autre protéine anti-apoptotique. Nos résultats montrent que Mcl-1, contrairement à Bcl-2, est davantage exprimé dans les plasmocytes de MM que dans les plasmocytes normaux et que cette hyper-expression est essentiellement cantonnée au compartiment le plus proliférant CD45 Fort. L'étude de corrélation entre l'expression de Mcl-1 et la prolifération ne montrent pas, contrairement à Bcl-2, de corrélation significative. Aussi, l'hyper-expression constitutive de Mcl-1, essentiellement dans le compartiment CD45 Fort, est probablement liée directement à la malignité intrinsèque de la tumeur. Nous avons aussi montré que l'expression de Mcl-1 est liée à l'activité de la maladie. En effet cette protéine est plus exprimée dans les MM en rechutes que dans les MM au diagnostic. Aussi, la protéine Mcl-1 à probablement une valeur pronostic dans la progression du MM.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment

AbstractAlthough osteolysis is a common complication in patients with multiple myeloma (MM), the biologic mechanisms involved in the pathogenesis of MM-induced bone disease are poorly understood. Two factors produced by stromal-osteoblastic cells seem critical to the regulation of bone resorption: osteoprotegerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiation and activity, whereas OPG inhibits these processes. The present study investigated whether myeloma cells affect physiologic OPG/OPGL balance in the bone marrow (BM) environment. Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG. In a coculture system, human myeloma cells up-regulated OPGL expression but strongly down-regulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels. This effect, which was dependent on cell-to-cell contact between myeloma cells and BMSCs or preOB, partially involved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens showed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that myeloma cells affect the OPG/OPGL ratio in the BM environment and tend to confirm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease