Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation

Pérez-Galán, Patricia; Mora-Jensen, Helena; Weniger, Marc A.; Shaffer, Arthur L.; Rizzatti, Edgar Gil; Chapman, Colby M.; Mo, Clifton C.; Stennett, Lawrence; Rader, Christoph; Liu, Poching; Raghavachari, Nalini; Stetler‐Stevenson, Maryalice; Yuan, Constance; Pittaluga, Stefania; Marić, Irina; Dunleavy, Kieron; Wilson, Wyndham H.; Staudt, Louis M.; Wiestner, Adrian

doi:10.1182/blood-2010-02-269514

Cited by 100 publications

(80 citation statements)

References 57 publications

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“…13,14 Leung-Hagesteijn et al 13 recently demonstrated that MM cells achieve bortezomib resistance via de-commitment to terminal plasma cell maturation, others have instead found that this resistance could be related to plasmacytic differentiation. 15 Nonetheless, the use of NAs during the induction phase followed by auto-SCT has been associated with improvement in the quality of responses, with a higher number of patients achieving VGPR or better, which in turn translates into a major benefit for OS and PFS. 6,12,16,17 Although auto-SCT after NAs induction can result in sustained responses in the majority of cases, still there are some patients relapsing within a year after auto-SCT and this group has poorly been characterized.…”

Section: Discussionmentioning

confidence: 99%

Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents

Jiménez-Zepeda

Reece

Trudel

et al. 2014

Bone Marrow Transplant

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The role of auto-SCT in the treatment of multiple myeloma (MM) in the era of novel agents continues to evolve. It is now clear that the depth of response and clinical outcomes have significantly improved as a result of the combination of these strategies. However, not all patients with MM who undergo auto-SCT are able to sustain a meaningful response and 20% of patients relapse shortly after auto-SCT. In this study, we aimed to assess the impact of early relapse (ER) after auto-SCT on OS for MM patients undergoing single auto-SCT who had received novel agent-based induction regimens. All consecutive patients with MM undergoing single auto-SCT from January 2002 to September 2012 who had novel induction therapy were evaluated. A total of 184 patients were identified. The median OS and PFS for the group of transplanted patients were 93 and 25.4 months, respectively. Median time to relapse was 17.2 months with 40% having relapsed at the time of analysis. ER (o 12 months post auto-SCT) was seen in 27 (36%) out of 75 patients who had relapsed, and median OS was significantly shorter than in those with non-ER. Multivariate analysis showed ER as the major independent prognostic factor for OS. On the basis of these findings, we conclude that not only attainment of a good response, but sustainability of it, appears to be a major prognostic variable in MM in the era of novel therapy. Patients with ER post auto-SCT should biologically be characterized in prospective studies to better understand the mechanisms of resistance associated with this particular entity.

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Section: Discussionmentioning

confidence: 99%

Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents

Jiménez-Zepeda

Reece

Trudel

et al. 2014

Bone Marrow Transplant

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“…Plasmacytic differentiation, driven by IRF4 overexpression, has been linked to bortezomib resistance in MCL [Perez-Galan et al 2011], while MYC is a direct IRF4 target in activated B cells and myeloma [Shaffer et al 2008]. Combining CPI203 with lenalidomide inhibited transcriptional overexpression of IRF4 and MYC and overcame bortezomib resistance in vivo [Moros et al 2014].…”

Section: Lymphomamentioning

confidence: 99%

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Chaidos

Caputo

Karadimitris

2015

Therapeutic Advances in Hematology

143

104

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Post-translational modifications of the nucleosomal histone proteins orchestrate chromatin organization and gene expression in normal and cancer cells. Among them, the acetylation of N-terminal histone tails represents the fundamental epigenetic mark of open structure chromatin and active gene transcription. The bromodomain and extra-terminal (BET) proteins are epigenetic readers which utilize tandem bromodomains (BRD) modules to recognize and dock themselves on the acetylated lysine tails. The BET proteins act as scaffolds for the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation. The recent discovery of small molecules capable of blocking their lysine-binding pocket is the first paradigm of successful pharmacological inhibition of epigenetic readers. JQ1 is a prototype benzodiazepine molecule and a specific BET inhibitor with antineoplastic activity both in solid tumours and haematological malignancies. The quinolone I-BET151 and the suitable for clinical development I-BET762 benzodiazepine were introduced in parallel with JQ1 and have also shown potent antitumour activity in preclinical studies. I-BET762 is currently being tested in early phase clinical trials, along with a rapidly growing list of other BET inhibitors. Unlike older epigenetic therapies, the study of BET inhibitors has offered substantial, context-specific, mechanistic insights of their antitumour activity, which will facilitate optimal therapeutic targeting in future. Here, we review the development of this novel class of epigenetic drugs, the biology of BET protein inhibition, the emerging evidence from preclinical work and early phase clinical studies and we discuss their potential role in the treatment of haematological malignancies.

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“…Bortezomib induces apoptosis in MCL through upregulation of the BH3-only protein NOXA (79). NOXA acts as a downstream effector of an integrated cellular stress response triggered by the accumulation of undegraded, polyubiquitinated proteins that induce endoplasmic reticulum stress and the generation of reactive oxygen species (80). Single-agent bortezomib therapy was shown to induce responses in 30%-50% of cases, even in patients who failed to respond to prior dose-intensive therapy or who had bulky disease (81).…”

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 99%

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

304

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation

Cited by 100 publications

References 57 publications

Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents

Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Molecular pathogenesis of mantle cell lymphoma

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