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Cited by 7Multiple Myeloma Research and TreatmentsProtein Degradation and InhibitorsChronic Lymphocytic Leukemia Research

The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients

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Barankiewicz, Joanna, Szumera-Ciećkiewicz, Anna, Salomon-Perzyński, Aleksander, Wieszczy, Paulina, Malenda, Agata, Garbicz, Filip, Prochorec-Sobieszek, Monika, Misiewicz-Krzemińska, Irena +2 more·2021·Journal of Clinical Medicine
DOI 10.3390/jcm10122683PMC PMC8235391
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Abstract

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins’ expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy.

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  • Endogenous CRBN expression is a strong predictor of IMiD efficacy.

    “Similarly, endogenous cRBN expression is a strong predictor of iMiD efficacy.”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Barankiewicz et al. 2021

    The Discussion reports that CRBN-positive multiple myeloma patients had better responses to thalidomide- or lenalidomide-based therapy. But it also describes CRBN expression as a potential predictive factor needing further evaluation, so calling it a strong predictor of IMiD efficacy overstates the paper’s conclusion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Higher CRBN expression levels alongside key components of the CRL4 CRBN complex, such as DDB1 and CUL4A, are associated with improved clinical responses.

    “Higher cRBN expression levels alongside key components of the cRl4 cRBN complex, such as DDB1 and cul4A, are associated with improved clinical responses (Barankiewicz et al. 2021).”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Barankiewicz et al. 2021

    Results §3.4 reports better responses to IMiD-based treatment in patients positive for CRBN or CUL4A. It also states that DDB1 expression showed no significant difference in treatment response, so the claim overextends the association to DDB1. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

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Authors
Barankiewicz, J., Szumera-Ciećkiewicz, A., Salomon-Perzyński, A., Wieszczy, P., Malenda, A., Garbicz, F., Prochorec-Sobieszek, M., Misiewicz-Krzemińska, I., Juszczyński, P., & Lech-Marańda, E.
Affiliations
  • Instytut Hematologii i Transfuzjologi (PL)
  • Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland
  • Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland
  • Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 02-781 Warsaw, Poland
Corresponding author
Barankiewicz, Joanna
ORCID
Venue
Journal of Clinical Medicine
Publisher
MDPI AG
Published
2021-06-18
Volume
10
Issue
12
Pages
2683
ISSN
2077-0383 (ISSN-L)
DOI
10.3390/jcm10122683
PMC
PMC8235391
OpenAlex
W3175954352
Cited by
7
References
3
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1
FWCI
0.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Narodowe Centrum Nauki (2014/3/B/NZ5/03160)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
multiple myeloma, immunomodulators, cereblon, CUL4A, DDB1, lenalidomide, thalidomide, treatment response prediction, prognosis, overall survival, progression-free survival, IKZF1, IKZF3, ubiquitination

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