International Journal of Hematological Disorders
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International Journal of Hematological Disorders. 2014, 1(1A), 13-20
DOI: 10.12691/ijhd-1-1A-3
Open AccessResearch Article

Cereblon and Its Role in the Treatment of Multiple Myeloma by Lenalidomide or Pomalidomide

Ota Fuchs1, , Radka Bokorová1, Martin Vostrý1, Arnošt Kostečka1 and Jaroslav Polák1

1Institute of Hematology and Blood Transfusion, Prague, Czech Republic

Pub. Date: December 09, 2014
(This article belongs to the Special Issue Plasma cell disorders )

Cite this paper:
Ota Fuchs, Radka Bokorová, Martin Vostrý, Arnošt Kostečka and Jaroslav Polák. Cereblon and Its Role in the Treatment of Multiple Myeloma by Lenalidomide or Pomalidomide. International Journal of Hematological Disorders. 2014; 1(1A):13-20. doi: 10.12691/ijhd-1-1A-3

Abstract

Cereblon (CRBN) is part of the cullin 4-containing E3 ubiquitin ligase complex (CRL4CRBN) and functions as a target of thalidomide and its analogs (lenalidomide and pomalidomide) known as immunomodulatory drugs (IMiDs). The CRBN gene consists of 1329 base pairs, 11 exons, and encodes a protein of 443 amino acids. Exons 10-11 code for the binding site of IMiDs and exons 5-7 for the binding site of DNA damage binding protein 1 (DDB1). CRBN consists of three sub-domains, the amino-terminal domain, the helical bundle domain involved in DDB1 binding and the carboxy-terminal domain harbouring IMiD– binding hydrophobic pocket CRBN in the absence of IMiDs binds to its endogenous substrate proteinsand it leads to ubiquitination of these substrates by the CRL4CRBN and their degradation by proteasomes. However, in the presence of IMiDs, CRBN binds new substrate proteins, transcription factors IKZF1 (IKAROS) and IKZF3 (AILOS), for drug-induced ubiquitination by the CRL4CRBN and next degradation in proteasomes. The administration of IMiDs alters the specificity of the CRL4CRBN and affects simultaneously the levels of two groups of substrate proteins. IMiDs upregulate the levels of endogenous substrates (MEIS2 and CRBN) and decrease the amounts of new substrates (IKAROS family proteins). In the meantime we do not know all possible substrates of the CRL4CRBN because it depends on the cell type and proteins expressed. IMiDs have the anti-proliferative, anti-angiogenic and immunomodulatory activities and are efficient in several hematological malignancies as multiple myeloma, chronic lymphocytic leukemia, mantle lymphoma and isolated del (5q) myelodysplastic syndrome. Targeted knockdown of IKAROS and AILOS causes the decrease of myeloma survival factor IRF4 (interferon regulatory factor 4) and c-myc with the decrease in cell viability in multiple myeloma cells and the increase of interleukin-2 in T-cells and their co-stimulation, both similar to that after IMiDs treatment.

Keywords:
cereblon cullin 4-containing E3 ubiquitin ligase complex Ikaros family immunomodulatory drugs lenalidomide multiple myeloma proteasome

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References:

[1]  Kunz W, Keller H, Muckter H. N-phthalyl-glutamic acid imide; experimental studies on a new synthetic product with sedative properties. Arzneim Forsch 1956; 6: 426-30.
 
[2]  McBride WG. Thalidomide and congenital abnormalities. Lancet 1961; 2: 1358.
 
[3]  Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med 1962; 267: 1184-92.
 
[4]  Miller MT, Stromland K. Teratogen update: thalidomide: a review with a focus on ocular findings and new potential uses. Teratology 1999; 60: 306-21.
 
[5]  Knobloch J, Ruther U. Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects. Cell Cycle 2008; 7: 1121-7.
 
[6]  Ito T, Handa H. Deciphering the mystery of thalidomide teratogenicity. Congenit Anom (Kyoto) 2012; 52: 1-7.
 
[7]  Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565-71.
 
[8]  Richardson P, Anderson K. Thalidomide and dexamethasone: a new standard of care for initial therapy in multiple myeloma. J Clin Oncol 2006; 24: 334-6.
 
[9]  Xu M, Hou Y, Sheng L, Peng J. Therapeutic effects of thalidomide in haematological disorders: a review. Front Med 2013; 7: 290-300.
 
[10]  Smith SM, Grinblatt D, Johnson JL, et al. Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: a phase II trial of the Cancer and Leukemia Group B. Br J Haematol 2008; 140: 313-9.
 
[11]  Wu H, Zhao C, Gu K, Jiao Y, Hao J, Sun G. Thalidomide plus chemotherapy exhibit enhanced efficacy in the clinical treatment of T-cell non-Hodgkin´s lymphoma: A prospective study of 46 cases. Mol Clin Oncol 2014; 2: 695-700.
 
[12]  Damaj G, Lefrère F, Delarue R, Varet B, Furman R, Hermine O. Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia 2003; 17: 1914-5.
 
[13]  Richardson SJ, Eve HE, Copplestone JA, Dyer MJ, Rule SA. Activity of thalidomide and lenalidomide in mantle cell lymphoma. Acta Haematol 2010; 123: 21-9.
 
[14]  Awan FT, Johnson AJ, Lapalombella R, et al. Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. Leuk Lymphoma 2010; 51: 27-38.
 
[15]  Pointon JC, Eagle G, Bailey J, Evans P, Allsup D, Greenman J. Thalidomide enhances cyclophosphamide and dexamethasone-mediated cytotoxicity towards cultured chronic lymphocytic leukaemia cells. Oncol Rep 2010; 24: 1315-21.
 
[16]  Giannopoulos K, Mertens D, Stilgenbauer S. Treating chronic lymphocytic leukemia with thalidomide and lenalidomide. Expert Opin Pharmacother 2011; 12: 2857-64.
 
[17]  Strupp C, Germing U, Aivado M, Misgeld E, Haas R, Gattermann N. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia 2002; 16: 1-6.
 
[18]  Invernizzi R, Travaglino E, Amici MD, et al. Thalidomide treatment reduces apoptosis levels in bone marrow cells from patients with myelodysplastic syndromes. Leuk Res 2005; 29: 641-7.
 
[19]  Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in longstanding refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98: 958-65.
 
[20]  Castelli R, Cassin R, Cannavó A, Cugno M. Immunomodulatory drugs: new options for the treatment of myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk 2013; 13: 1-7.
 
[21]  Corral LG, Haslett PA, Muller GV, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol1999; 163: 380-6.
 
[22]  Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Thalidomide and lenalidomide: mechanism-based potential drug combinations. Leuk Lymphoma 2008; 49: 1238-45.
 
[23]  Kotla V, Goel S, Nischal S, et al.Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol2009; 2: 36.
 
[24]  Sedlarikova L, Kubiczkova L, Sevcikova S, Hajek R. Mechanism of immunomodulatory drugs in multiple myeloma. Leuk Res 2012; 36: 1218-24.
 
[25]  Chang DH,Liu D, Klimek V,et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide.: therapeutic implications. Blood2006; 108: 618-21.
 
[26]  Galustian C, Meyer B, Labarte MC,et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother. 2009; 58: 1033-45.
 
[27]  Davies F, Baz R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev 2010; 24 (Suppl.1): S13-S19.
 
[28]  DredgeK, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87: 1166-72.
 
[29]  Dredge K, Horsfall R, Robinson SP, et al. Orally administrated lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvascular Res. 2005; 69: 56-63.
 
[30]  Dankbar B, Paadro T, Leo R, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood. 2000; 95: 2630-6.
 
[31]  Escoubet-Lozach L, Lin IL, Jensen-Pergakes K,et al. Pomalidomide and lenalidomide induce p21 WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res 2009; 69: 7347-56.
 
[32]  Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: Therapeutic implications. Blood. 2002; 99: 4525-30.
 
[33]  Chang X, Zhu Y, Shi C, Stewart AK. Mechanism of immunomodulatory drugs´ action in the treatment of multiple myeloma. Acta Biochim Biophys Sin. 2014; 46: 240-53.
 
[34]  Lacy MQ, Hayman SR, Gertz MA et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 2009; 27: 5008-14.
 
[35]  Lacy MQ, Hayman SR, Gertz MA et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010; 24: 1934-9.
 
[36]  Schey S, Ramasamy K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs 2011; 20: 691-700.
 
[37]  Richardson PG, Siegel D, Baz Ret al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013; 121: 1961-7.
 
[38]  Leleu X, Attal M, Arnulf B et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome. 2009-02. Blood 2013; 121: 1968-75.
 
[39]  San Miguel J, Weisel K, Moreau P et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised open-label phase 3 trial. Lancet Oncol 2013; 14: 1055-66.
 
[40]  Richardson PG, Siegel D, Vij R et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014; 123: 1826-32.
 
[41]  Clark SM, Steinbach A, Clemmons AB. Pomalidomide for the treatment of multiple myeloma. J Adv Pract Oncol 2014; 5: 51-6.
 
[42]  Ito T, Ando H, Suzuki T, et al. Identificationof a primary target of thalidomideteratogenicity. Science 2010; 327: 1345-150.
 
[43]  Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012; 26: 2326-35.
 
[44]  Chang XB, Stewart AK. What is the functional role of the thalidomide binding protein cereblon? Int J Biochem Mol Biol 2011; 2: 287-94.
 
[45]  Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67: 425-79.
 
[46]  Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 2001; 70: 503-33.
 
[47]  Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev2002; 82: 373-428.
 
[48]  Pickart CM, Cohen RE. Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol 2004; 5: 177-87.
 
[49]  Hershko A. Review: Nobel Lecture. The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 2005; 12: 1191-7.
 
[50]  CiechanoverA. Intracellular protein degradation from a vague idea through the lysosome and the ubiquitin-proteasome system and on to human diseases and drug targeting: Nobel Lecture, December 8, 2004. Ann N Y Acad Sci 2007, 1116, 1-28.
 
[51]  Rose I. Review: Nobel Lecture. Ubiquitin at Fox Chase. Cell Death Differ 2005; 12: 1162-6.
 
[52]  Ciechanover A. Tracing the history of the ubiquitin proteolytic system: the pioneering article. Biochem Biophys Res Commun 2009; 387: 1-10.
 
[53]  Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ 1999; 6: 303-13.
 
[54]  Wójcik C. Regulation of apoptosis by the ubiquitin and proteasome pathway. J Cell Mol Med 2002; 6: 25-48.
 
[55]  Kinyamu HK, Chen J, Archer TK. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J Mol Endocrinol 2005; 34: 281-97.
 
[56]  Sun Y. E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia 2006; 8: 645-54.
 
[57]  Kitagawa K, Kotake Y, Kitagawa M. Ubiquitin-mediated control of oncogene and tumor suppressor gene products. Cancer Sci 2009; 100: 1374-81.
 
[58]  Bassermann T, Eichner R, Pagano M. The ubiquitin proteasome system-Implications for cell cycle control and the targeted treatment of cancer. Biochim Biophys Acta 2014; 1843: 150-62.
 
[59]  Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta 2014; 1843: 47-60.
 
[60]  Ciechanover A, Stanhill A. The complexity of recognition of ubiquitinated substrates by 26 S proteasome. Biochim Biophys Acta 2014; 1843: 86-96.
 
[61]  Golab J, Bauer TM, Daniel V, Naujokat C. Role of the ubiquitin-proteasome pathway in the diagnosis of human diseases. Clin Chim Acta 2004; 340: 27-40.
 
[62]  Nalepa G, Rolfe M, Wade Harper J. Drug discovery in the ubiquitin-proteasome system. Nature Rev Drug Disc 2006; 5: 596-613.
 
[63]  Krӧnke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343: 301-5.
 
[64]  Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014; 343: 305-9.
 
[65]  Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN. Br J Haematol 2014; 164: 811-21.
 
[66]  Stewart AK. How thalidomide works against cancer. Science 2014; 343: 256-7.
 
[67]  Fischer ES, Böhm K, Lydeard JR et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 2014; 512: 49-53.
 
[68]  Chamberlain PP, Lopez-Girona A, Miller K et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nature Struct Mol Biol 2014.
 
[69]  Zhu YX, Braggio E, Shi CX et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 2014; 124: 536-45.
 
[70]  Shaffer AL, Tolga Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature 2008; 454: 226-31.
 
[71]  Shaffer AL, Tolga Emre NC, Romesser PB, Staudt LM. IRF4: Immunity. Malignancy! Therapy? Clin Cancer Res 2009; 15: 2954-61.
 
[72]  Lopez-Girona A, Heintel D, Zhang LH, et al. Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 2011; 154: 325-36.
 
[73]  Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell1999; 96: 635-44.
 
[74]  Micel LN, Tentler JJ, Smith PG, Eckhardt GS. Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies. J Clin Oncol 2013; 31: 1231-8.
 
[75]  Petroski MD, Deshales RJ. Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6: 9-20.
 
[76]  Jin J, Arias EE, Chen J, Wade Harper J, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 2006; 23: 709-21.
 
[77]  Li T, Chen X, Garbutt KC, et al. Structure of DDB1 in complex with a ParamyxovirusV protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 2006; 124, 105-17.
 
[78]  Angers S, Li T, Yi X, MacCoss MJ, Moon RT,Zheng N. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 2006; 590-3.
 
[79]  Lee J, Zhou P. DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Mol Cell 2007; 26: 775-80.
 
[80]  Catic A. Culling for survival. Blood 2008; 112: 211-12.
 
[81]  Waning DL, Li B, Jia N,et al. Cul 4A is required for hematopoietic cell viability and its deficiency leads to apoptosis.Blood 2008; 112: 320-9.
 
[82]  Jackson S, Xiong Y. CRL4s: the CUL4-RING E3 ubiquitin ligases. Trends Bichem Sci 2009; 34: 562-70.
 
[83]  Sugasawa K. The CUL4 enigma: Culling DNA repair factors. Mol Cell 2009; 34: 403-404.
 
[84]  Lee J, Zhou P. Pathogenic role of the CRL4 ubiquitin ligase in human disease. Front Oncol 2012; 2: 1-7.
 
[85]  Zhao Y, Sun Y. Cullin-RING ligases as attractive anti-cancer targets. Curr Pharm Des 2013; 19: 3215-25.
 
[86]  Choo YY, Boh BK, Lou JJ, et al. Characterization of the role of COP9 signalosome in regulating cullin E3 ubiquitin ligase activity. Mol Biol Cell 2011; 22: 4706-15.
 
[87]  Shortt J, Hsu AK, Martin BP, et al. The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound. Cell Rep 2014; 7, 1009-19.
 
[88]  He YJ, McCall CM, Hu J, et al. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev 2006; 20: 2949-54.
 
[89]  Iovine B, Iannella ML, Bevilacqua MA. Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions. Int J Biochem Cell Biol 2011; 43: 1664-7.
 
[90]  Komatsu M, Kageyama S, Ichimura Y. p62/SQSTM1/A170: physiology and pathology. Pharmacol Res 2012; 66: 457-62.
 
[91]  Rogov V, Dötsch V, Johansen T, Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins from the molecular basis for selective autophagy. Mol Cell 2014; 53: 167-78.
 
[92]  Racevskis J, Dill A, Stockert R, Fineberg SA. Cloning of a novel nuclear guanosine 5´-triphosphate binding protein autoantigen from a breast tumor. Cell Growth Differ 1996; 7: 271-80.
 
[93]  Tsvetkov P, Adamovich Y, Elliott E, Shaul Y. The E3 ligase STUB1/CHIP regulates NAD(P)H: quinone oxidoreductase 1 (NQO1) accumulation in aged brain, a process impaired in certain Alzheimer patients. J Biol Chem 2011; 286: 8839-45.
 
[94]  Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997; 15: 155-76.
 
[95]  Kipally J, Renold A, Kim J, Georgopoulos K. Repression by Ikaros and Ailos is mediated through histone deacetylase complexes. EMBO J 1999; 18: 3090-100.
 
[96]  Schmitt C, Tonnelle C, Dalloul A, et al. Ailos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation.Apoptosis 2002; 7: 277-84.
 
[97]  Rao KN, Smuda C, Gregory GD, et al. Ikaros limits basophil development by suppressing C/EBP-α expression. Blood 2013; 122: 2572-81.
 
[98]  Malinge S, Thiollier C, Chion TM, et al. Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood 2013; 121: 2440-51.
 
[99]  Bai R, Li D, Shi Z, et al. Clinical significance of ankyrin repeat domain 12 expression in colorectal cancer. J Exp Clin Cancer Res 2013; 32: 35.
 
[100]  Christiansen A, Dyrskjøt L. The functional role of the novel biomarker karyopherin α2 (KPNA2) in cancer. Cancer Lett 2013; 331: 18-23.
 
[101]  Umegaki-Arao N, Tamai K, Nimura K, et al. Karyopherin alpha2 is essential for rRNA transcription and protein synthesis in proliferative keratinocytes. PLOS One 2013; 8: e76416.
 
[102]  Zerucha T, Prince VE. Cloning and developmental expression of a zebrafish meis 2 homeobox gene. Mech Dev 2000, 102: 247-50.
 
[103]  Biemar F, Devos N, Martial JA, et al. Cloning and expression of the TALE superclass homeobox Meis 2 gene during zebrafish embryonic development. Mech Dev 2001, 109: 427-31.
 
[104]  Bjerke GA, Hyman-Walsh C, Wotton D. Cooperative transcriptional activation by Klf4, Meis2, and Pbx1. Mol Cell Biol 2011; 31: 3723-33.
 
[105]  Zha Y, Xia Y, Ding J et al. MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression. Cell Death Dis 2014, 5: e1417.
 
[106]  Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011, 118: 4771-9.
 
[107]  Broyl A, Kuiper R, van Duin M, et al. High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood 2013; 121: 624-7.
 
[108]  Heintel, D, Rocci A, Ludwig H, et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 2013; 161: 748-51.
 
[109]  Lodé L, Amiot M, Maiga S, Touzeau C, Menard A, Magrangeas F, Minvielle S, Pellat-Deceunynck C, Bene MC, Moreau P. Cereblon expression in multiple myeloma: not ready for prime time. Br J Haematol 2013; 163: 282-4.
 
[110]  Gandhi AK, Mendy D, Waldman M, Chen G, Rychak E, Miller K, Gaidarova S, Ren Y, Wang M, Breider M, Carmel G, Mahmoudi A, Jackson P, Abbasian M, Cathers BE, Schafer PH, Daniel TO, Lopez-Girona A, Thakurta A, Chopra R. Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br J Haematol. 2014; 164: 233-44.
 
[111]  Pearse RN. IMiDs: Not for the CRBN weak. Leuk Res 2014; 38: 21-2.
 
[112]  Schuster SR, Kortuem KM, Zhu YX, et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res 2014, 38: 23-8.
 
[113]  Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma 2013; 54: 683-7.
 
[114]  Lionetti M, Agnelli L, Lombardi L, et al. MicroRNAs in the pathobiology of multiple myeloma. Curr Cancer Drug Targets 2012; 12: 823-37.
 
[115]  Wu P, Agnelli L, Walker BA, et al. Improved risk stratification in myeloma using a microRNA-based classifier. Br J Haematol 2013; 162: 348-59.
 
[116]  Bi C, Chng WJ. MicroRNA: important player in the pathobiology of multiple myeloma. Biomed Res Inst 2014; 2014: 521586.
 
[117]  Greenberg AJ, Walters DK, Kumar SK, et al. Responsiveness of cytogenetically discrete human myeloma cell lines to lenalidomide: lack of correlation with cereblon and interferon regulatory factor 4 expression levels. Eur J Haematol 2013; 91: 504-13.
 
[118]  Lonial S, Boise LH. The future of drug development and therapy in myeloma. Semin Oncol 2013; 40: 652-658.
 
[119]  Boise LH, Kaufman JL, Bahlis NJ, et al. The Tao of myeloma. Blood 2014, prepublished online August 5, 2014.
 
[120]  Li S, Pal R, Monaghan SA,et al. IMiD immunomodulatory compounds block C/EBPβ translation through eIF4E down-regulation resulting in inhibition of MM. Blood 2011; 117: 5157-65.
 
[121]  Chesi M, Robbiani DF, Sebag M, et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 2008; 13. 167-180.
 
[122]  Chesi M, Matthews GM, Garbitt VM, et al. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 2012; 120:376-385.
 
[123]  Affer M, Chesi M, Chen WD, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 2014; 28: 1725-35.
 
[124]  Walker BA, Wardell CP, Brioli A, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J 2014; 4: e191.
 
[125]  Licht JD, Shortt J, Johnstone R. From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. Cancer Cell 2014; 25: 9-11.
 
[126]  Holstein SA. The evolving tale of immunomodulatory drugs and cereblon. Clin Pharmacol Ther 2014, Aug. 21.