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      SUMOylation inhibition enhances multiple myeloma sensitivity to lenalidomide

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          Abstract

          Despite the potent effect of lenalidomide (Len) in multiple myeloma (MM) treatment, patients develop Len resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms mediating Len resistance. Our study identified SUMOylation as a potential mechanism regulating Len resistance in MM. Len-resistant MM cell line MMR10R presented much higher SUMO E1 (SAE2) expression and more global SUMOylation than Len-sensitive MM1S cell line. SUMOylation inhibition by using TAK-981, a novel and specific SUMO E1 inhibitor, significantly enhances myeloma sensitivity to Len in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Len combination has been validated using primary relapsing MM patient samples. Overexpression of IRF4 and c-Myc is a major mechanism of Len resistance. Len showed limited effect on IRF4 and c-Myc level in Len-resistance cell line, but TAK-981 treatment reduced IRF4 and c-Myc expression in Len-resistant line and caused further decrease when combined with Len. We found SUMOylation inhibition decreases IRF4 at transcriptional and post-translational level. SUMOylation inhibition reduced DOT1L with decreased methylation of histone H3 lysine 79, to suppress IRF4 gene transcription. SUMOylation inhibition also reduced IRF4 protein level by enhancing degradation. Overall, our data revealed SUMOylation inhibition enhances Len sensitivity through downregulating IRF4.

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          Most cited references39

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          Drug combination studies and their synergy quantification using the Chou-Talalay method.

          This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively.
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            Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

            Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
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              The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.

              Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
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                Author and article information

                Contributors
                lidu@coh.org
                srosen@coh.org
                Journal
                Cancer Gene Ther
                Cancer Gene Ther
                Cancer Gene Therapy
                Nature Publishing Group US (New York )
                0929-1903
                1476-5500
                25 March 2022
                25 March 2022
                2023
                : 30
                : 4
                : 567-574
                Affiliations
                [1 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, ; Duarte, CA USA
                [2 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, ; Duarte, CA USA
                [3 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Department of Hematology and Stem Cell Transplant, , Beckman Research Institute of City of Hope, ; Duarte, CA USA
                [4 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Department of Hematology, , Xiangya Hospital, Central South University, ; Changsha, China
                [5 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, City of Hope Comprehensive Cancer Center, City of Hope National Medical Center, ; Duarte, CA USA
                Author information
                http://orcid.org/0000-0002-4215-3801
                http://orcid.org/0000-0002-8818-7724
                Article
                450
                10.1038/s41417-022-00450-9
                10104776
                35338347
                42a8addd-25d2-49cb-aec3-08c16aa06291
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 August 2021
                : 18 January 2022
                : 24 February 2022
                Categories
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                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2023

                Oncology & Radiotherapy
                cancer therapeutic resistance,myeloma
                Oncology & Radiotherapy
                cancer therapeutic resistance, myeloma

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