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

Zhu, Yuan Xiao; Braggio, Esteban; Shi, Chao; Kortuem, K. Martin; Bruins, Laura A.; Schmidt, Jessica; Chang, Xiu Bao; Langlais, Paul; Luo, Moulun; Jedlowski, Patrick; LaPlant, Betsy; Laumann, Kristina; Fonseca, Rafaël; Bergsagel, P. Leif; Mıkhael, Joseph; Lacy, Martha Q.; Champion, Mia D.; Stewart, A. Keith

doi:10.1182/blood-2014-02-557819

Cited by 191 publications

(247 citation statements)

References 35 publications

Supporting

Mentioning

234

Contrasting

Order By: Relevance

“…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%

“…When wt CRBN is introduced and overexpressed, OCI-MY5 regains IMiD sensitivity. 12 We introduced and overexpressed all 3 CRBN mutations into OCI-MY5 in independent experiments, as well as the wt CRBN (positive control) and the viral vector alone (negative control). Cell viability was assessed by using an MTT assay (in triplicate) after a 6-day treatment with increasing doses of lenalidomide (Figure 4).…”

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%

See 2 more Smart Citations

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

Kortüm

Elias

Hanafiah

et al. 2016

Blood

Self Cite

210

191

View full text Add to dashboard Cite

• 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

show abstract

Section: Crbn-associated Mutationsmentioning

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

Self Cite

210

191

View full text Add to dashboard Cite

show abstract

“…For example, after seminal work identifying cereblon (CRBN) as the binding protein of immunomodulatory drugs (IMiDs) [which, in PCs, leads to the ubiquitination of substrates such as Ikaros (IKZF1) and Aiolos (IKZFe)], more recent studies have already shown that CRBN and IKZF1 levels correlate with survival in MM patients treated with pomalidomide and dexamethasone. 12,13 To fully describe this intrinsic resistance, we need to consider the contribution of the interaction of malignant PCs with the BM microenvironment, which provides a sanctuary for myeloma cells by promoting proliferation and blocking apoptosis, thereby enabling tumor progression and the eventual emergence of drug resistance. 4 Therefore, down-regulating the interaction between tumor cells and the microenvironment can potentially halt cell growth and proliferation and be of benefit to patients.…”

Section: Mechanism Of Resistancementioning

confidence: 99%

Multiple myeloma: a model for scientific and clinical progress

Miguel

2014

Hematology

View full text Add to dashboard Cite

Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second-and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease. Learning Objectives• To understand that myeloma should no longer be considered as a single entity • To understand that better tools for diagnosis and monitoring treatment efficacy are being implemented • To understand that the treatment goal is to find the best possible balance among efficacy, toxicity, and cost

show abstract

“…1 CBMs bind to a specific pocket in the protein cereblon (CRBN) [2][3][4] an interaction which enhances the E3-ubiquitin-ligase activity of the CRBN/Cul4A/Cul4B/DDB1/Roc1 complex. As a result, the downstream substrates of CRBN, Ikaros (IKZF1) and Aiolos (IKZF3), important regulators in T-and B-cell development, are more efficiently ubiquitinated and degradated.…”

mentioning

confidence: 99%

Proteasome inhibitors block Ikaros degradation by Lenalidomide in Multiple Myeloma

et al. 2015

View full text Add to dashboard Cite

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

Cited by 191 publications

References 35 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

Multiple myeloma: a model for scientific and clinical progress

Proteasome inhibitors block Ikaros degradation by Lenalidomide in Multiple Myeloma

Contact Info

Product

Resources

About