The clinical significance of cereblon expression in multiple myeloma

Schuster, Steven R.; Kortuem, K. Martin; Zhu, Yuan Xiao; Braggio, Esteban; Shi, Chao; Bruins, Laura A.; Schmidt, Jessica; Ahmann, Greg; Kumar, Shaji; Rajkumar, S. Vincent; Mıkhael, Joseph; LaPlant, Betsy; Champion, Mia D.; Laumann, Kristina; Barlogie, Bart; Fonseca, Rafaël; Bergsagel, P. Leif; Lacy, Martha Q.; Stewart, A. Keith

doi:10.1016/j.leukres.2013.08.015

Cited by 89 publications

(98 citation statements)

References 22 publications

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“…Although a role of mutant IRF4 in IMiD resistance remains to be established, CRBN is the central mediator of IMiD action, and its expression is essential for the anti-MM effects of IMiDs. [12][13][14][15][16] Notably, all CRBN-mutated patients (n 5 6) and 10 (91%) of 11 of the CRBN pathway-mutated patients were unresponsive to IMiD-based treatment at the time of tumor sampling (the IMiD-refractory status of 1 patient was unknown) suggesting an association of these mutations with IMiD response. Thus far, CRBN mutations are largely absent in the publically available MM sequencing data that, of note, include mostly untreated patients.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, the cereblon pathway, important for the anti-MM action of IMiDs, [12][13][14]17 was found mutated in almost one-quarter of patients (22%). This includes CRBN (12%), CUL4B (6%), IRF4 (4%), and IKZF1 (2%) (Figure 1; supplemental Figure 1).…”

Section: Crbn-associated Mutationsmentioning

confidence: 99%

“…Cereblon (CRBN) was recently identified as being essential for the anti-MM activity of IMiDs. [11][12][13][14][15][16][17][18] To date, the reported incidence of mutations in proteasome subunits, the CRBN pathway, or the steroid receptor is low, and mutations in these genes, except in single case studies 19,20 or in vitro cell line analyses, 20,21 have not yet been identified as a major source of primary or acquired drug resistance in larger MM data sets.…”

Section: Introductionmentioning

confidence: 99%

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Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Kortüm

Elias

Hanafiah

et al. 2016

Blood

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• The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM.• Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response. (Blood. 2016;128(9):1226-1233

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Section: Discussionmentioning

confidence: 99%

Section: Crbn-associated Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Kortüm

Elias

Hanafiah

et al. 2016

Blood

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194

190

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“…13,14 Finally, we have reported that CRBN expression is highly predictive of response and survival outcomes after pomalidomide therapy. 15 However, a majority of patients with low CRBN levels have no evidence of genomic mutation, thus transcriptional or posttranscriptional factors may influence CRBN gene expression and responsiveness to IMiD therapy. 16 Despite these findings, the intermediaries and facilitators of cell death after CRBN and IMiD interaction that ultimately degrade IRF4 and MYC are as yet not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma

Zhu

Braggio

Shi

et al. 2014

Blood

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“…The action of IMiDs appears to be mediated via binding to CRBN with activation of its associated E3 ubiquitin ligase and subsequent proteasomal degradation of Ikaros. 5,6 Furthermore, low CRBN and IZKF1 levels are associated with IMiD resistance, 3,4,7,8 but other parallel pathways or downstream events that enhance or preclude drug responsiveness are unknown.In the present study, a druggable genome short interfering RNA (siRNA) screen was used to identify 63 genes whose loss of expression enhances lenalidomide sensitivity in human MM cells. The strongest sensitizer was the kinase, RSK2.…”

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confidence: 99%

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Zhu

Yin

Bruins

et al. 2015

Blood

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• High-throughput RNAi screening identified lenalidomide sensitizer genes, including RSK2, RAB, peroxisome, and potassium channel family members.• Knockdown or inhibition of RSK2 synergized with lenalidomide to induce myeloma cytotoxicity and downregulation of interferon regulatory factor 4 and MYC.To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-k-B kinase-a (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-a or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy. (Blood. 2015;125(3): [483][484][485][486][487][488][489][490][491] IntroductionThe immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are broadly used in the treatment of patients with multiple myeloma (MM) and have produced significant clinical advances in both newly diagnosed and advanced disease.1,2 However, only 30% of relapsed MM patients respond to single agent IMiD therapy and most patients eventually develop drug resistance. The underlying mechanisms defining this nonresponsiveness are largely unknown. Recently, Cereblon (CRBN) and Ikaros/Aiolos (IZKF1 and IZKF3) were identified as the molecular targets of IMiDs in MM 3-6 via their ability to induce cytotoxicity by inhibiting interferon regulatory factor 4 (IRF4) and MYC. The action of IMiDs appears to be mediated via binding to CRBN with activation of its associated E3 ubiquitin ligase and subsequent proteasomal degradation of Ikaros. 5,6 Furthermore, low CRBN and IZKF1 levels are associated with IMiD resistance, 3,4,7,8 but other parallel pathways or downstream events that enhance or preclude drug responsiveness are unknown.In the present study, a druggable genome short interfering RNA (siRNA) screen was used to identify 63 genes whose loss of expression enhance...

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The clinical significance of cereblon expression in multiple myeloma

Cited by 89 publications

References 22 publications

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

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