MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA–eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (−)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013;122:3884–91.
Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature. 2014;511:488–92.
Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151:68–79.
Scott DW, King RL, Staiger AM, Ben-Neriah S, Jiang A, Horn H, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018;131:2060–4.
Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533–7.
Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28:3360–5.
Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, et al. Double-hit B-cell lymphomas. Blood. 2011;117:2319–31.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.
Sarkozy C, Traverse-Glehen A, Coiffier B. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas. Lancet Oncol. 2015;16:e555–e67.
Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114:2273–9.
Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.
Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017;28:1776–87.
Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord JP, de La Motte Rouge T, et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov. 2016;6:492–500.
Pawar A, Gollavilli PN, Wang S, Asangani IA. Resistance to BET inhibitor leads to alternative therapeutic vulnerabilities in castration-resistant prostate cancer. Cell Rep. 2018;22:2236–45.
Kurimchak AM, Shelton C, Duncan KE, Johnson KJ, Brown J, O’Brien S, et al. Resistance to BET bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer. Cell Rep. 2016;16:1273–86.
Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008;456:971–5.
Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14:261–78.
Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5’-untranslated regions of eukaryotic mRNAs. Science. 2016;352:1413–6.
Topisirovic I, Svitkin YV, Sonenberg N, Shatkin AJ. Cap and cap-binding proteins in the control of gene expression. Wiley Inter Rev Rna. 2011;2:277–98.
Ravitz MJ, Chen L, Lynch M, Schmidt EV. c-myc repression of TSC2 contributes to control of translation initiation and Myc-induced transformation. Cancer Res. 2007;67:11209–17.
Elkon R, Loayza-Puch F, Korkmaz G, Lopes R, van Breugel PC, Bleijerveld OB, et al. Myc coordinates transcription and translation to enhance transformation and suppress invasiveness. EMBO Rep. 2015;16:1723–36.
Lucas DM, Edwards RB, Lozanski G, West DA, Shin JD, Vargo MA, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009;113:4656–66.
Manier S, Huynh D, Shen YJ, Zhou J, Yusufzai T, Salem KZ, et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci Transl Med. 2017;9:389.
Pan L, Woodard JL, Lucas DM, Fuchs JR, Kinghorn AD. Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. Nat Prod Rep. 2014;31:924–39.
Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118:2651–60.
Wiegering A, Uthe FW, Jamieson T, Ruoss Y, Huttenrauch M, Kuspert M, et al. Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 2015;5:768–81.
Robert F, Roman W, Bramoulle A, Fellmann C, Roulston A, Shustik C, et al. Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma. Proc Natl Acad Sci USA. 2014;111:13421–6.
Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras AC, Crosby K, et al. Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs. RNA. 2008;14:1318–27.
Pettersson F, Del Rincon SV, Miller WH Jr.. Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond. Expert Opin Ther Targets. 2014;18:1035–48.
Yang T, Buchan HL, Townsend KJ, Craig RWMCL-1. a member of the BLC-2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation. J Cell Physiol. 1996;166:523–36.
Raynaud FI, Orr RM, Goddard PM, Lacey HA, Lancashire H, Judson IR, et al. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J Pharm Exp Ther. 1997;281:420–7.
Pestova TV, Shatsky IN, Hellen CU. Functional dissection of eukaryotic initiation factor 4F: the 4A subunit and the central domain of the 4G subunit are sufficient to mediate internal entry of 43S preinitiation complexes. Mol Cell Biol. 1996;16:6870–8.
Svitkin YV, Pause A, Haghighat A, Pyronnet S, Witherell G, Belsham GJ, et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5’ secondary structure. RNA. 2001;7:382–94.
Chu J, Galicia-Vazquez G, Cencic R, Mills JR, Katigbak A, Porco JA Jr., et al. CRISPR-mediated drug-target validation reveals selective pharmacological inhibition of the RNA helicase, eIF4A. Cell Rep. 2016;15:2340–7.
Pelletier J, Graff J, Ruggero D, Sonenberg N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 2015;75:250–63.
Iwasaki S, Iwasaki W, Takahashi M, Sakamoto A, Watanabe C, Shichino Y, et al. The Translation inhibitor rocaglamide targets a bimolecular cavity between eIF4A and polypurine RNA. Mol Cell. 2019;73:P738–748.E9.
Iwasaki S, Floor SN, Ingolia NT. Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor. Nature. 2016;534:558–61.
Chambers JM, Lindqvist LM, Webb A, Huang DC, Savage GP, Rizzacasa MA. Synthesis of biotinylated episilvestrol: highly selective targeting of the translation factors eIF4AI/II. Org Lett. 2013;15:1406–9.
Andreou AZ, Klostermeier D. The DEAD-box helicase eIF4A: paradigm or the odd one out? RNA Biol. 2013;10:19–32.
Oblinger JL, Burns SS, Akhmametyeva EM, Huang J, Pan L, Ren Y, et al. Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas. Neuro Oncol. 2016;18:1265–77.
Galicia-Vazquez G, Cencic R, Robert F, Agenor AQ, Pelletier J. A cellular response linking eIF4AI activity to eIF4AII transcription. RNA. 2012;18:1373–84.
Chu J, Cencic R, Wang W, Porco JA Jr., Pelletier J. Translation inhibition by rocaglates is independent of eIF4E phosphorylation status. Mol cancer Ther. 2016;15:136–41.
den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A, et al. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010;116:1498–505.
Ren Y, Bi C, Zhao X, Lwin T, Wang C, Yuan J, et al. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest. 2018;128:5517–30.
Malka-Mahieu H, Newman M, Desaubry L, Robert C, Vagner S. Molecular pathways: the eIF4F translation initiation complex-new opportunities for cancer treatment. Clin Cancer Res. 2017;23:21–5.
Lin CJ, Malina A, Pelletier J. c-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. Cancer Res. 2009;69:7491–4.
Cope CL, Gilley R, Balmanno K, Sale MJ, Howarth KD, Hampson M, et al. Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation. J Cell Sci. 2014;127(Pt 4):788–800.
Duncan R, Hershey JW. Identification and quantitation of levels of protein synthesis initiation factors in crude HeLa cell lysates by two-dimensional polyacrylamide gel electrophoresis. J Biol Chem. 1983;258:7228–35.
Peters TL, Tillotson J, Yeomans AM, Wilmore S, Lemm E, Jimenez-Romero C, et al. Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity. Clin Cancer Res. 2018;24:4256–70.
Cencic R, Pelletier J. Hippuristanol - a potent steroid inhibitor of eukaryotic initiation factor 4A. Transl (Austin). 2016;4:e1137381.
Bonetti P, Testoni M, Scandurra M, Ponzoni M, Piva R, Mensah AA, et al. Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood. 2013;122:2233–41.
Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med. 2014;4. pii: a014282.
Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood. 2014;123:2451–9.
Basso K, Dalla-Favera R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol. 2010;105:193–210.
Bi C, Zhang X, Lu T, Zhang X, Wang X, Meng B, et al. Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas. Haematologica. 2017;102:755–64.
Yueh H, Gao Q, Porco JA Jr., Beeler AB. A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues. Bioorg Med Chem. 2017;25:6197–202.
Stone SD, Lajkiewicz NJ, Whitesell L, Hilmy A, Porco JA Jr. Biomimetic kinetic resolution: highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products. J Am Chem Soc. 2015;137:525–30.
Rodrigo CM, Cencic R, Roche SP, Pelletier J, Porco JA. Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies. J Med Chem. 2012;55:558–62.
Wang W, Cencic R, Whitesell L, Pelletier J, Porco JA Jr. Synthesis of Aza-rocaglates via ESIPT-mediated (3+2) photocycloaddition. Chemistry. 2016;22:12006–10.
Saradhi UV, Gupta SV, Chiu M, Wang J, Ling Y, Liu Z, et al. Characterization of silvestrol pharmacokinetics in mice using liquid chromatography-tandem mass spectrometry. AAPS J. 2011;13:347–56.
We would like to thank Jerry Pelletier at the McGill University for his valuable advice and comments to the paper. We thank Joseph Gera (Greater Los Angeles VA Healthcare System, CA, USA) for providing us the pRF plasmid. We thank Dirk Eick (Helmholtz Zentrum München, Munich, Germany) for providing us P493-6 cell line. We thank John Chan (City of Hope, CA, USA) for providing NKYS cell line. We thank Richard J. Ford (MD. Anderson, TX, USA) for providing CJ cell line. We thank Sophie Alvarez and Michael Naldrett at the Proteomics and Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska-Lincoln, supported by the Nebraska Research Initiative for performing the proteomics analysis. We sincerely thank Wang Yuzhuo (Vancouver, British Columbia) at the Living Tumor Laboratory for providing the MYC/BCL2 double expression PDX model. We thank David M. Weinstock and Dana-Farber’s bank of patient-derived tumor xenografts (Dana-Farber Cancer Institute, MA, USA) for providing the MYC/BCL2 double-translocation PDX line.
This study was supported in part by a pilot grant and a lymphoma program grant from the Fred & Pamela Buffett Cancer Center at UNMC (to KF), the National Cancer Institute (P30 CA036727), Nebraska Department of Health and Human Services (LB506-18-22 to KF), and the National Institutes of Health (R35 GM118173 and R24 GM111625 to JAP, Jr).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhang, X., Bi, C., Lu, T. et al. Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas. Leukemia 34, 138–150 (2020). https://doi.org/10.1038/s41375-019-0503-z