Determination of Plasma Cell Secreting Potential as an Index of Maturity of Myelomatous Cells and a Strong Prognostic Factor

Symeonidis, Argiris; Kouraklis-Symeonidis, Alexandra; Grouzi, Elisabeth; Zolota, Vassiliki; Melachrinou, Maria; Kourea, Kalliroy; Fragopanagou, E.; Giannakoulas, Nikolaos; Seimeni, U.; Tiniakou, M.; Matsouka, P.; Zoumbos, Nicholas

doi:10.1080/1042819021000002938

Cited by 8 publications

(7 citation statements)

References 31 publications

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“…In general, it is tempting to speculate that sensitivity to proteasome inhibitors may, at least in part, stem from reduced proteolytic capacity, or increased proteasomal workloads, or both situations combined. In line with this idea, the extent of Ig secretion, assessed by dividing serum paraprotein levels by marrow tumour cellularity, has been proposed as a prognostic factor for MM 55. Furthermore, in MM lines, the level of Ig synthesis was shown to correlate with apoptotic sensitivity to proteasome inhibitors 56.…”

Section: Discussionmentioning

confidence: 99%

Dampening Ab responses using proteasome inhibitors following in vivo B cell activation

et al. 2008

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Upon encounter with Ag, B lymphocytes undergo terminal differentiation into plasma cells, highly specialized Ab secretors that mediate humoral immune responses. Profound changes adapt cellular morphology and proteome to the new secretory functions. Although a massive secretory activity is expected to require an efficient ubiquitin-proteasome degradation system, recent in vitro studies have surprisingly revealed that the proteasome function sharply decreases during plasma cell development, thereby limiting the proteolytic capacity. We challenged this paradigm in mouse models of B cell activation, and observed that following polyclonal activation, proteasome activity decreases more than previously reported in vitro. This decrease is linked to enhanced apoptosis after treatment with the potent anti-myeloma proteasome inhibitor PS-341. Accordingly, in vivo treatment with PS-341 decreases Ab titres in T-dependent and -independent mouse immunization models. This study provides the rationale for limiting the activity of Ab-secreting cells in vivo by impacting proteasome function. IntroductionUpon encounter with Ag and co-stimulatory signals provided by T cells, small resting B lymphocytes activate a profound structural and functional metamorphosis involving proliferation and differentiation into Absecreting plasma cells, terminally differentiated elements capable of secreting thousands of Ab per second, so as to ensure rapid defense [1][2][3]. This complex program also entails generation of memory cells, isotype switch, and affinity maturation. While a minority of plasma cells home to the bone marrow and live longer, the vast majority, particularly those producing IgM, die by apoptosis after a few days of intense Ig secretion [4][5][6]. Although extrinsic factors are crucial to shape the proper environment for long-lived plasma cells [7,8], little is known of the molecular events that cause apoptosis of short-lived Ab secretors.Recently, wide-scope studies demonstrated that plasma cell differentiation entails profound proteome changes that upgrade the cellular secretory capacity. For example, endoplasmatic reticulum (ER) resident chaperones and folding assistants responsible for protein quality control in the secretory pathway are upregulated in a concerted fashion prior to cargo protein production [9]. Indeed, XBP-1, a key transcription factor of the unfolded protein response, the multifaceted adaptive response to ER stress, is fundamental for plasma cell differentiation [10,11]. XBP-1 promotes the * These authors contributed equally to this work. ** These authors contributed equally to this work. Surprisingly, instead, we recently reported that during plasma cell differentiation, when Ab production becomes maximal, the relative amount and proteolytic activity of proteasomes dramatically decrease, potentially contributing to plasma cell death [17]. The finding that cells carrying out massive protein synthesis and secretion do not deploy an adequate proteasomal apparatus poses an apparent paradox. Indeed, proteasomes ...

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Section: Discussionmentioning

confidence: 99%

Dampening Ab responses using proteasome inhibitors following in vivo B cell activation

et al. 2008

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“…The load vs capacity model offers a potential explanation, reinforced by recent results demonstrating correlations between the extent of protein production and sensitivity to bortezomib [63,64].…”

Section: An Exploitable Stress Against Cancermentioning

confidence: 93%

Managing and exploiting stress in the antibody factory

2007

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Like us, our cells have evolved strategies to cope with, and sometimes utilize, stress. Molecular analyses of plasma cell biogenesis, lifestyle and death suggest that protein synthesisdependent stress is utilised to integrate differentiation, function and lifespan control. Plasma cells are short-lived professional secretory cells, each of them capable of releasing several thousands antibodies per second. Their differentiation from B lymphocytes entails the spectacular enlargement of the endoplasmic reticulum (ER), finalized to sustain massive Ig production. Nonetheless, symptoms of ER stress are evident, and the UPR-related transcription factor XBP-1 is essential for differentiation. Surprisingly, the development of such an efficient factory is matched by a decrease in proteasomes. The unbalanced load/ capacity ratio leads to accumulation of polyubiquitinated molecules and predisposes plasma cells to apoptosis. Exuberant antibody secretion imposes considerable stress on metabolic and redox homeostasis. Collectively, these stressful conditions may link plasma cell death to antibody production, providing a molecular counter for secreted molecules, as well as an explanation for the peculiar sensitivity of myeloma cells towards proteasome inhibitors.

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“…In many other neoplasms, therapeutic advances have been related to the availability of plasma biomarkers with prognostic and therapeutic significance which may complement imaging studies. Examples of these include prostate specific antigen (PSA), gonadotropins, and serum immunoglobulins in prostate, testicular, and hematologic malignancies, respectively (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%