Skip to main content
SpringerLink
Log in

The molecular mechanism of thalidomide analogs in hematologic malignancies

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells. The underlying molecular mechanisms for these pleiotropic effects remained obscure until the identification of the cereblon (CRBN) E3 ubiquitin ligase as the primary target of thalidomide and its analogs in 2010. Binding of thalidomide or lenalidomide increases the affinity of CRBN to the transcription factors IKZF1 and IKZF3 and casein kinase 1α (CK1α). Ubiquitination and degradation of these neo-substrates results in IL-2 release and growth arrest of multiple myeloma and MDS cells. The discovery of this previously undescribed mechanism for an approved drug provides a proof-of-concept for the development of new therapeutics that exploit ubiquitin ligases for specific degradation of disease-associated proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. McBride WG (1963) The teratogenic action of drugs. Med J Aust 2:689–692

    CAS  PubMed  Google Scholar 

  2. Lenz W, Knapp K (1962) Thalidomide embryopathy. Dtsch Med Wochenschr 87:1232–1242

    Article  CAS  PubMed  Google Scholar 

  3. Sheskin J (1965) Thalidomide in the treatment of LEPRA reactions. Clin Pharmacol Ther 6:303–306

    Article  CAS  PubMed  Google Scholar 

  4. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G (1991) Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173:699–703

    Article  CAS  PubMed  Google Scholar 

  5. Haslett PA, Corral LG, Albert M, Kaplan G (1998) Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 187:1885–1892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163:380–386

    CAS  PubMed  Google Scholar 

  7. D'Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085

    Article  PubMed  PubMed Central  Google Scholar 

  8. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M et al (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571

    Article  CAS  PubMed  Google Scholar 

  9. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR (2006) Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431–436

    Article  CAS  PubMed  Google Scholar 

  10. Muller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G, Stirling DI (1996) Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J Med Chem 39:3238–3240

    Article  CAS  PubMed  Google Scholar 

  11. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA et al (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142

    Article  CAS  PubMed  Google Scholar 

  12. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132

    Article  CAS  PubMed  Google Scholar 

  13. Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD, Streetly M, Dalgleish AG (2004) Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 22:3269–3276

    Article  CAS  PubMed  Google Scholar 

  14. Chanan-Khan A, Porter CW (2006) Immunomodulating drugs for chronic lymphocytic leukaemia. Lancet Oncol 7:480–488

    Article  CAS  PubMed  Google Scholar 

  15. Habermann TM, Lossos IS, Justice G, Vose JM, Wiernik PH, McBride K, Wride K, Ervin-Haynes A, Takeshita K, Pietronigro D et al (2009) Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 145:344–349

    Article  CAS  PubMed  Google Scholar 

  16. Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E et al (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood 126:779–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549–557

    Article  CAS  PubMed  Google Scholar 

  18. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465

    Article  CAS  PubMed  Google Scholar 

  19. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Canizo C et al (2011) A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118:3765–3776

    Article  CAS  PubMed  Google Scholar 

  20. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327:1345–1350

    Article  CAS  PubMed  Google Scholar 

  21. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M et al (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26:2326–2335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL et al (2011) Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118:4771–4779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X et al (2014) Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–305

    Article  PubMed  Google Scholar 

  24. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–309

    Article  CAS  PubMed  Google Scholar 

  25. Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A et al (2014) 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 CRL4(CRBN.). Br J Haematol 164:811–821

    Article  CAS  PubMed  Google Scholar 

  26. Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, Chamberlain PP, Mani DR, Man HW, Gandhi AK et al (2015) Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523:183–188

    Article  PubMed  PubMed Central  Google Scholar 

  27. Petzold G, Fischer ES, Thoma NH (2016) Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4 ubiquitin ligase. Nature DOI. doi:10.1038/nature16979

    Google Scholar 

  28. Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM et al (2014) Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512:49–53

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, Corral LG, Ren YJ, Wang M et al (2014) Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. doi:10.1038/nsmb.2874

    PubMed  Google Scholar 

  30. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63:1927–1931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee KM, Jo S, Kim H, Lee J, Park CS (2011) Functional modulation of AMP-activated protein kinase by cereblon. Biochim Biophys Acta 1813:448–455

    Article  CAS  PubMed  Google Scholar 

  32. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (2008) Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics 9:219–223

    Article  CAS  PubMed  Google Scholar 

  33. Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B et al (2016) Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol Cell 61:809–820

    Article  CAS  PubMed  Google Scholar 

  34. Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE, Chang XB, Langlais P, Luo M, Jedlowski P et al (2014) Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 124:536–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yoshida T, Georgopoulos K (2014) Ikaros fingers on lymphocyte differentiation. Int J Hematol 100:220–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A (1994) The Ikaros gene is required for the development of all lymphoid lineages. Cell 79:143–156

    Article  CAS  PubMed  Google Scholar 

  37. Winandy S, Wu P, Georgopoulos K (1995) A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83:289–299

    Article  CAS  PubMed  Google Scholar 

  38. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB et al (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–764

    Article  CAS  PubMed  Google Scholar 

  39. Nuckel H, Frey UH, Sellmann L, Collins CH, Duhrsen U, Siffert W (2009) The IKZF3 (Aiolos) transcription factor is highly upregulated and inversely correlated with clinical progression in chronic lymphocytic leukaemia. Br J Haematol 144:268–270

    Article  PubMed  Google Scholar 

  40. Cortes M, Georgopoulos K (2004) Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med 199:209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H et al (2008) IRF4 addiction in multiple myeloma. Nature 454:226–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bjorklund CC, Lu L, Kang J, Hagner PR, Havens CG, Amatangelo M, Wang M, Ren Y, Couto S, Breider M et al (2015) Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood Cancer J 5:e354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lopez-Girona A, Heintel D, Zhang LH, Mendy D, Gaidarova S, Brady H, Bartlett JB, Schafer PH, Schreder M, Bolomsky A et al (2011) Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 154:325–336

    Article  CAS  PubMed  Google Scholar 

  44. Georgopoulos K, Moore DD, Derfler B (1992) Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science 258:808–812

    Article  CAS  PubMed  Google Scholar 

  45. Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A, Kozoriz D, Weiner HL, Quintana FJ (2010) Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 11:846–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Steensma DP (2015) Myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc 90:969–983

    Article  PubMed  Google Scholar 

  47. Tefferi A, Vardiman JW (2009) Myelodysplastic syndromes. N Engl J Med 361:1872–1885

    Article  CAS  PubMed  Google Scholar 

  48. Ebert BL (2011) Molecular dissection of the 5q deletion in myelodysplastic syndrome. Semin Oncol 38:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M (2005) The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal 17:675–689

    Article  CAS  PubMed  Google Scholar 

  50. Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, Chu LP, McConkey ME, Kramann R, Mullally A et al (2014) Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 26:509–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A et al (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29:1971–1979

    Article  PubMed  Google Scholar 

  52. Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, Habdank M, Kugler C-M, Holzmann K, Gaidzik VI et al (2011) TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. doi:10.1182/blood-2011-08-375758

    PubMed  Google Scholar 

  53. Kelaidi C, Park S, Brechignac S, Mannone L, Vey N, Dombret H, Aljassem L, Stamatoullas A, Ades L, Giraudier S et al (2008) Treatment of myelodysplastic syndromes with 5q deletion before the lenalidomide era; the GFM experience with EPO and thalidomide. Leuk Res 32:1049–1053

    Article  CAS  PubMed  Google Scholar 

  54. Moreno-Aspitia A, Colon-Otero G, Hoering A, Tefferi A, Niedringhaus RD, Vukov A, Li CY, Menke DM, Geyer SM, Alberts SR (2006) Thalidomide therapy in adult patients with myelodysplastic syndrome. A North Central Cancer Treatment Group phase II trial. Cancer 107:767–772

    Article  CAS  PubMed  Google Scholar 

  55. Fratta ID, Sigg EB, Maiorana K (1965) Teratogenic effects of thalidomide in rabbits, rats, hamsters, and mice. Toxicol Appl Pharmacol 7:268–286

    Article  CAS  PubMed  Google Scholar 

  56. Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M, Stewart AK, Johnstone RW, Bergsagel PL (2012) Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 120:376–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ (2001) Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A 98:8554–8559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE (2015) DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–1381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K et al (2015) Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol 22:755–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, Hines J, Crews CM (2015) Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed Engl. doi:10.1002/anie.201507634

    Google Scholar 

  61. Broyl A, Kuiper R, van Duin M, van der Holt B, el Jarari L, Bertsch U, Zweegman S, Buijs A, Hose D, Lokhorst HM et al (2013) High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood 121:624–627

    Article  CAS  PubMed  Google Scholar 

  62. Heintel D, Rocci A, Ludwig H, Bolomsky A, Caltagirone S, Schreder M, Pfeifer S, Gisslinger H, Zojer N, Jager U et al (2013) High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 161:695–700

    Article  CAS  PubMed  Google Scholar 

  63. Jonasova A, Bokorova R, Polak J, Vostry M, Kostecka A, Hajkova H, Neuwirtova R, Siskova M, Sponerova D, Cermak J et al (2015) High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. Eur J Haematol 95:27–34

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Esther Obeng for critical reading of our manuscript. This work was supported by an Emmy-Noether Fellowship (Kr3886/2-1) from the Deutsche Forschungsgemeinschaft (DFG).

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany

    Stefanie Lindner & Jan Krönke

Authors
  1. Stefanie Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan Krönke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan Krönke.

Ethics declarations

Conflict of interest

J.K. received honoraria from Celgene. S.L. declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lindner, S., Krönke, J. The molecular mechanism of thalidomide analogs in hematologic malignancies. J Mol Med 94, 1327–1334 (2016). https://doi.org/10.1007/s00109-016-1450-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-016-1450-z

Keywords

Search

Navigation