دورية أكاديمية
أعرض في EDS

MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.

التفاصيل البيبلوغرافية
العنوان: MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.
المؤلفون: Davis LN; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Walker ZJ; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Reiman LT; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Parzych SE; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Stevens BM; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Jordan CT; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Forsberg PA; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Sherbenou DW; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
المصدر: Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Jul 15; Vol. 30 (14), pp. 3023-3035.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Denville, NJ : The Association, c1995-
مواضيع طبية MeSH: Multiple Myeloma*/drug therapy , Multiple Myeloma*/pathology , Multiple Myeloma*/immunology , CD8-Positive T-Lymphocytes*/immunology , CD8-Positive T-Lymphocytes*/drug effects , CD8-Positive T-Lymphocytes*/metabolism , Proto-Oncogene Proteins c-myc*/genetics , Proto-Oncogene Proteins c-myc*/metabolism , Drug Resistance, Neoplasm* , Ikaros Transcription Factor*/metabolism , Ikaros Transcription Factor*/genetics , Thalidomide*/analogs & derivatives , Thalidomide*/pharmacology , Immunomodulating Agents*/pharmacology , Interferon Regulatory Factors*/metabolism , Interferon Regulatory Factors*/genetics, Humans ; Cell Line, Tumor ; Lenalidomide/pharmacology ; Lenalidomide/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Female ; Male
مستخلص: Purpose: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context.
Experimental Design: Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed exvivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry.
Results: We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs.
Conclusions: Our study supports the concept that MYC represents an Achilles' heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.
(©2024 American Association for Cancer Research.)
References: Blood. 2022 Mar 31;139(13):2024-2037. (PMID: 34936696)
Science. 2002 Jul 5;297(5578):102-4. (PMID: 12098700)
Blood. 2016 Sep 1;128(9):1226-33. (PMID: 27458004)
Blood. 2021 Jan 14;137(2):232-237. (PMID: 33443552)
Cancer Discov. 2015 Oct;5(10):1024-39. (PMID: 26382145)
Blood Cancer Discov. 2024 Jan 8;5(1):34-55. (PMID: 37767768)
Blood. 2011 Nov 3;118(18):4771-9. (PMID: 21860026)
Mol Biol Rep. 2019 Aug;46(4):4631-4643. (PMID: 31093875)
Clin Cancer Res. 2023 Dec 1;29(23):4784-4796. (PMID: 37463058)
J Immunol. 1999 Jul 1;163(1):380-6. (PMID: 10384139)
Leukemia. 2021 Jul;35(7):2114-2118. (PMID: 33149265)
Lancet Oncol. 2013 Oct;14(11):1055-1066. (PMID: 24007748)
Cell. 2017 Jul 27;170(3):564-576.e16. (PMID: 28753430)
Science. 2014 Jan 17;343(6168):305-9. (PMID: 24292623)
Leukemia. 2020 Apr;34(4):1197-1201. (PMID: 31719682)
Nat Rev Clin Oncol. 2022 Jan;19(1):23-36. (PMID: 34508258)
Blood. 2021 Nov 4;138(18):1721-1726. (PMID: 34115836)
Clin Exp Immunol. 2014 Aug;177(2):439-53. (PMID: 24712857)
Cell Stem Cell. 2021 Apr 1;28(4):623-636.e9. (PMID: 33476575)
Blood. 2008 Oct 15;112(8):3362-72. (PMID: 18658027)
Blood Cancer Discov. 2024 Jan 8;5(1):56-73. (PMID: 37934799)
Leuk Res. 2014 Jan;38(1):23-8. (PMID: 24129344)
Nat Chem Biol. 2020 Nov;16(11):1208-1217. (PMID: 32958952)
Nature. 2008 Jul 10;454(7201):226-31. (PMID: 18568025)
Leukemia. 2020 Jan;34(1):322-326. (PMID: 31439946)
Leukemia. 2012 Nov;26(11):2326-35. (PMID: 22552008)
Lancet Haematol. 2022 Nov;9(11):e822-e832. (PMID: 36209764)
Nat Commun. 2022 Nov 9;13(1):6782. (PMID: 36351945)
Immunol Lett. 2004 Feb 15;91(2-3):239-45. (PMID: 15019295)
Science. 2014 Jan 17;343(6168):301-5. (PMID: 24292625)
Blood Adv. 2020 Apr 28;4(8):1628-1639. (PMID: 32311014)
Cancer Cell. 2019 Nov 11;36(5):483-497.e15. (PMID: 31679823)
Blood Cancer J. 2015 Oct 02;5:e354. (PMID: 26430725)
Nature. 2009 Apr 9;458(7239):732-6. (PMID: 19360080)
Blood. 2019 Jul 11;134(2):160-170. (PMID: 31043423)
Blood. 2023 Jun 8;141(23):2841-2852. (PMID: 36877894)
Blood. 2018 Nov 15;132(20):2166-2178. (PMID: 30228232)
Leukemia. 2019 Sep;33(9):2266-2275. (PMID: 30858549)
J Immunol. 2007 Apr 1;178(7):4112-9. (PMID: 17371966)
Cell Rep. 2015 Jul 14;12(2):244-57. (PMID: 26146082)
Oncotarget. 2015 Sep 15;6(27):24218-29. (PMID: 26155942)
Blood. 2023 Feb 9;141(6):620-633. (PMID: 36223594)
Blood. 2002 Jun 15;99(12):4525-30. (PMID: 12036884)
Front Immunol. 2019 Dec 13;10:2759. (PMID: 31921102)
Genomics Proteomics Bioinformatics. 2022 Jun;20(3):587-596. (PMID: 35085776)
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. (PMID: 22451913)
Cancer Cell. 2010 Nov 16;18(5):485-98. (PMID: 21035406)
Nat Med. 2023 Mar;29(3):632-645. (PMID: 36928817)
J Immunol. 2002 Jun 1;168(11):5538-50. (PMID: 12023349)
معلومات مُعتمدة: K08 CA222704 United States CA NCI NIH HHS; T32 TR004367 United States TR NCATS NIH HHS; T32TR004367 Colorado Clinical and Translational Sciences Institute (CCTSI); K08CA222704 National Cancer Institute (NCI)
المشرفين على المادة: 0 (Proto-Oncogene Proteins c-myc)
D2UX06XLB5 (pomalidomide)
148971-36-2 (Ikaros Transcription Factor)
4Z8R6ORS6L (Thalidomide)
0 (interferon regulatory factor-4)
0 (Immunomodulating Agents)
0 (Interferon Regulatory Factors)
0 (IKZF1 protein, human)
0 (IKZF3 protein, human)
0 (MYC protein, human)
F0P408N6V4 (Lenalidomide)
تواريخ الأحداث: Date Created: 20240509 Date Completed: 20240715 Latest Revision: 20240718
رمز التحديث: 20240718
مُعرف محوري في PubMed: PMC11250500
DOI: 10.1158/1078-0432.CCR-24-0256
PMID: 38723281
قاعدة البيانات: MEDLINE
الوصف
تدمد:1557-3265
DOI:10.1158/1078-0432.CCR-24-0256