Multiple myeloma (MM) is an aggressive, debilitating and deadly hematological malignancy, arising from the clonal expansion of plasma cells at multiple sites in the bone marrow. Recently, MM proved sensitive to a new class of drugs, proteasome inhibitors (PI), currently in phase 3 clinical trial. PI induce apoptosis selectively in MM cells, but the molecular bases of this therapeutic effect remain undetermined. We explored the mechanisms underlying sensitivity of MM to PI on plasma cells differentiated in vitro from the murine B lymphoma I.29 A+ and ex vivo from primary mouse B cells. We found that during differentiation apoptosis correlates with the Ig-synthetic load. As apoptosis increases, the relative amount of proteasomal subunits and the resulting proteolytic activity dramatically decrease, thus denying the demand for a higher degradative capacity when antibody production becomes maximal. The excessive load for the reduced proteolytic capacity causes accumulation of poly-ubiquitinated proteins and stabilization of endogenous proteasomal substrates such as the UPR mediator Xbp1, the NF-kB inhibitor Ik-Balpha and the pro-apoptotic Bcl-2 relatives Bim and Bax, two proteins critical in limiting B lymphocyte lifespan and activity. Accumulation of these proteins critically exaggerates endoplasmic reticulum (ER) stress, thus predisposing plasma cells to apoptosis upon treatment with PI. A similar scenario can be reproduced in HeLa cells, a non-B tumoral line, by driving Ig-A chain over-expression, which causes proteasomal overload, apoptotic sensitivity to proteasome inhibitors and eventually spontaneous apoptosis, thereby establishing a cause–effect relationship between the synthetic load and cell death. Our results suggest that a developmental program allows plasma cells to count the integral of produced Ig, linking death to protein production, thus ending the humoral immune response upon accomplishment of its goal. Based on our data, we propose that the high efficacy of PI ABSTRACTS / Bone 36 (2005) S103–S479 S215 against MM is due, to a significant extent, to overloading the cell’s degradative capacity, a key component of the stress response, already challenged by misfolded chains generated as a side product of intense Ig synthesis. This model provides a framework for attempting to achieve tumour cell destruction through modulation of stress in MM.
Impaired proteasomal capacity as the target of proteasome inhibitors in multiple myeloma
CASCIO, Paolo;CERRUTI, Fulvia;
2005-01-01
Abstract
Multiple myeloma (MM) is an aggressive, debilitating and deadly hematological malignancy, arising from the clonal expansion of plasma cells at multiple sites in the bone marrow. Recently, MM proved sensitive to a new class of drugs, proteasome inhibitors (PI), currently in phase 3 clinical trial. PI induce apoptosis selectively in MM cells, but the molecular bases of this therapeutic effect remain undetermined. We explored the mechanisms underlying sensitivity of MM to PI on plasma cells differentiated in vitro from the murine B lymphoma I.29 A+ and ex vivo from primary mouse B cells. We found that during differentiation apoptosis correlates with the Ig-synthetic load. As apoptosis increases, the relative amount of proteasomal subunits and the resulting proteolytic activity dramatically decrease, thus denying the demand for a higher degradative capacity when antibody production becomes maximal. The excessive load for the reduced proteolytic capacity causes accumulation of poly-ubiquitinated proteins and stabilization of endogenous proteasomal substrates such as the UPR mediator Xbp1, the NF-kB inhibitor Ik-Balpha and the pro-apoptotic Bcl-2 relatives Bim and Bax, two proteins critical in limiting B lymphocyte lifespan and activity. Accumulation of these proteins critically exaggerates endoplasmic reticulum (ER) stress, thus predisposing plasma cells to apoptosis upon treatment with PI. A similar scenario can be reproduced in HeLa cells, a non-B tumoral line, by driving Ig-A chain over-expression, which causes proteasomal overload, apoptotic sensitivity to proteasome inhibitors and eventually spontaneous apoptosis, thereby establishing a cause–effect relationship between the synthetic load and cell death. Our results suggest that a developmental program allows plasma cells to count the integral of produced Ig, linking death to protein production, thus ending the humoral immune response upon accomplishment of its goal. Based on our data, we propose that the high efficacy of PI ABSTRACTS / Bone 36 (2005) S103–S479 S215 against MM is due, to a significant extent, to overloading the cell’s degradative capacity, a key component of the stress response, already challenged by misfolded chains generated as a side product of intense Ig synthesis. This model provides a framework for attempting to achieve tumour cell destruction through modulation of stress in MM.
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