IKZF1/3 and CRL4CRBN E3 ubiquitin ligase mutations and resistance to immunomodulatory drugs in multiple myeloma
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The work was supported by the Deutsche Forschungsgemeinschaft (KFO216), the IZKF, the\n\t\t\t\t BTHA and the CDW Stiftung (KMK). UM was supported by a grant of the German Excellence\n\t\t\t\t Initiative to the Graduate School of Life Sciences, University of Würzburg.
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Up to one-third of patients refractory to pomalidomide treatment present with various types of CRBN alterations.
“Accumulating data has shown that up to one-third of patients refractory to pomalidomide treatment present with various types of CRBN alterations41,42,49.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [41]
A mutation in CRBNH397 was identified in a multiple myeloma patient who presented refractory to IMiD treatment.
“Furthermore, a mutation in CRBNH397 was also identified in a multiple myeloma (MM) patient who presented refractory to IMiD treatment 41.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [41]
In multiple myeloma, resistance to IMiDs such as pomalidomide and lenalidomide includes genomic alterations in both the target protein (IKZF1/IKZF3) and components of the CRBN ligase machinery.
“Similarly, in the clinical setting in multiple myeloma, resistance to IMiDs such as pomalidomide and lenalidomide has been shown to include genomic alterations in both the target protein (IKZF1/IKZF3) and components of the CRBN ligase machinery102,103.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [103]
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Cites
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · see citing works
Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy
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Self-citationHeterogeneity of genomic evolution and mutational profiles in multiple myeloma
Bolli, N., Avet-Loiseau, H., Wedge, D. C., Van Loo, P., Alexandrov, L. B., Martincorena, I., Dawson, K. J., Iorio, F., Nik-Zainal, S., Bignell, G. R., et al. (2014) · Nature Communications · doi:10.1038/ncomms3997 · Cited by 875 · see citing works
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SDM: a server for predicting effects of mutations on protein stability
Pandurangan, A. P., Ochoa‐Montaño, B., Ascher, D. B., & Blundell, T. L. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx439 · Cited by 501 · see citing works
The Molecular Basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture, Targeting, and Activation
Fischer, E. S., Scrima, A., Böhm, K., Matsumoto, S., Lingaraju, G. M., Faty, M., Yasuda, T., Cavadini, S., Wakasugi, M., Hanaoka, F., et al. (2011) · Cell · doi:10.1016/j.cell.2011.10.035 · Cited by 460 · see citing works
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Self-citationCereblon binding molecules in multiple myeloma
Kortüm, K. M., Zhu, Y. X., Shi, C., Jedlowski, P. M., & Stewart, A. K. (2015) · Blood Reviews · doi:10.1016/j.blre.2015.03.003 · Cited by 53 · see citing works
Self-citationKortüm, K. M., Langer, C., Monge, J., Bruins, L. A., Zhu, Y. X., Shi, C. X., Jedlowski, P. M., Egan, J. B., Ojha, J., Bullinger, L., et al. (2015) · Annals of Hematology · doi:10.1007/s00277-015-2344-9 · Cited by 51 · see citing works
Self-citationTargeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in ‐17p high risk disease
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PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
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Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche
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Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders
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- Authors
- Barrio, S., Munawar, U., Zhu, Y. X., Giesen, N., Shi, C.-X., Viá, M. D., Sanchez, R., Bruins, L., Demler, T., Müller, N., Haertle, L., Garitano, A., Steinbrunn, T., Danhof, S., Cuenca, I., Barrio-Garcia, C., Braggio, E., Rosenwald, A., Martinez-Lopez, J., Rasche, L., Raab, M. S., Stewart, A. K., Einsele, H., Stühmer, T., & Kortüm, K. M.
- Affiliations
- Universitätsklinikum Würzburg (DE)
- Comprehensive Cancer Center Mainfranken (DE)
- Mayo Clinic in Arizona (US)
- German Cancer Research Center (DE)
- Universidad Complutense de Madrid (ES)
- Ludwig-Maximilians-Universität München (DE)
- University of Würzburg (DE)
- Mayo Clinic (US)
- ORCID
- Venue
- Haematologica
- Published
- 2019-09-26
- Volume
- 105
- Issue
- 5
- Pages
- e237-e241
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC7193510
- OpenAlex
- W2975659787
- Cited by
- 67
- References
- 13
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 19 · 2021: 7 · 2020: 4
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KFO-216)
- Julius-Maximilians-Universität Würzburg
- Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg
- National Cancer Institute (R01CA183968, P50CA186781)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- multiple myeloma, cereblon, IKZF1, IKZF3, ubiquitin ligase
- MeSH terms
- Pharmaceutical Preparations, Humans, Multiple Myeloma, Mutation, Thalidomide, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Receptors, Interleukin-17
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