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

Autor:	Zhu YX; Division of Hematology-Oncology and., Braggio E; Division of Hematology-Oncology and., Shi CX; Division of Hematology-Oncology and., Kortuem KM; Division of Hematology-Oncology and., Bruins LA; Division of Hematology-Oncology and., Schmidt JE; Division of Hematology-Oncology and., Chang XB; Department of Biochemistry & Molecular Biology, College of Medicine, Mayo Clinic, Scottsdale, AZ;, Langlais P; Department of Biochemistry & Molecular Biology, College of Medicine, Mayo Clinic, Scottsdale, AZ;, Luo M; Center for Metabolic and Vascular Biology, Arizona State University, Tempe, AZ;, Jedlowski P; Division of Hematology-Oncology and., LaPlant B; Division of Biomedical Statistics and Informatics and., Laumann K; Division of Biomedical Statistics and Informatics and., Fonseca R; Division of Hematology-Oncology and., Bergsagel PL; Division of Hematology-Oncology and., Mikhael J; Division of Hematology-Oncology and., Lacy M; Division of Hematology, Mayo Clinic, Rochester, MN; and., Champion MD; Division of Hematology-Oncology and Division of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, AZ., Stewart AK; Division of Hematology-Oncology and.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2014 Jul 24; Vol. 124 (4), pp. 536-45. Date of Electronic Publication: 2014 Jun 09.
DOI:	10.1182/blood-2014-02-557819
Abstrakt:	Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes; however, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation and a translocation that upregulates IRF4, an IKZF target. Clinical relevance of CRBN-binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0/11 responses in the lowest expression quartile). CRBN, IKZF1, and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN-binding proteins and demonstrates that in addition to CRBN, IKZF1, and KPNA2, expression can predict survival outcomes. (© 2014 by The American Society of Hematology.)
Databáze:	MEDLINE
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