Evidence map›Paper›PMID 26430725›Full record

ArticleBlood cancer journal2015

Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4.

C C Bjorklund, L Lu, J Kang, P R Hagner, C G Havens, M Amatangelo, M Wang, Y Ren, S Couto, M Breider and 6 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Blood cancer journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
118citing papers in PubMed, 2 pooled it
7.1field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

118 citing papers in PubMed, 2 syntheses or guidelines pooled it, 215 citations in OpenAlex.

  1. Pooled it
  2. Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2019
    Guideline
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  19. The Direction of Modern Therapies in Waldenström Macroglobulinaemia.Journal of cellular and molecular medicine · 2025
    Review
  20. [IKZF3/Aiolos and tumors].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025
    Review

58 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 1 institution in 1 country.

C C BjorklundTranslational Development, Celgene Corporation, Summit, NJ, USA.
L LuTranslational Development, Celgene Corporation, Summit, NJ, USA.
J KangTranslational Development, Celgene Corporation, Summit, NJ, USA.
P R HagnerTranslational Development, Celgene Corporation, Summit, NJ, USA.
C G HavensTranslational Development, Celgene Corporation, Summit, NJ, USA.
M AmatangeloTranslational Development, Celgene Corporation, Summit, NJ, USA.
M WangCelgene Corporation, San Diego, CA, USA.
Y RenCelgene Corporation, San Diego, CA, USA.
S CoutoCelgene Corporation, San Diego, CA, USA.
M BreiderCelgene Corporation, San Diego, CA, USA.
Y NingCelgene Corporation, San Diego, CA, USA.
A K GandhiTranslational Development, Celgene Corporation, Summit, NJ, USA.
T O DanielTranslational Development, Celgene Corporation, Summit, NJ, USA.
R ChopraTranslational Development, Celgene Corporation, Summit, NJ, USA.
A KlippelTranslational Development, Celgene Corporation, Summit, NJ, USA.
A G ThakurtaTranslational Development, Celgene Corporation, Summit, NJ, USA.
Bristol-Myers Squibb (Switzerland) · CH

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.

Indexed as

Antineoplastic AgentsApoptosisCell Line, TumorCell ProliferationDown-RegulationFlow CytometryGene Knockdown TechniquesHumansIkaros Transcription FactorImmunoblottingImmunohistochemistryInterferon Regulatory Factor-4Interferon Regulatory FactorsLenalidomideMultiple MyelomaProto-Oncogene Proteins c-mycAntineoplastic AgentsIkaros Transcription FactorIKZF1 protein, humanIKZF3 protein, humanInterferon Regulatory Factor-4Interferon Regulatory FactorsLenalidomideMYC protein, humanpomalidomideProto-Oncogene Proteins c-mycRNA, Small InterferingThalidomide

Identifiers

PMID26430725
PMCPMC4635186
OpenAlexW2125477622

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.