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Northwestern University Feinberg School of Medicine
Borden Lab

Research

4e, PML, dapi, 4E+PML, ov microscopic images

Our team seeks to shed light on how cells become cancerous, with a particular focus on the disconnect between the transcriptome and the proteome — much of which occurs at the RNA-processing level. Here we explore how dysregulated RNA metabolism drives and shapes cancer, focusing on acute myeloid leukemia (AML).

RNA metabolism can be hijacked by cancer cells to rewrite (for example, through splicing) and/or amplify the message sent from DNA without requiring mutations or changes in transcription. We utilize the eukaryotic translation initiation factor (eIF4E) as an exemplar for our studies as it acts in multiple steps of mRNA processing and is consistently present in both the nucleus and cytoplasm of plants, animals and fungi.

In the nucleus, eIF4E binds thousands of transcripts and influences multiple stages of RNA processing, including capping, splicing, 3′-end processing and mRNA export, in addition to its well-established role in cytoplasmic protein synthesis. Through the capacity to re-write and amplify certain mRNAs, mRNA processing and translation can literally change the surface of the cell, imbuing it with the capacity to crawl, traverse membrane barriers and even produce extracellular vesicles that also play roles in metastases.

We use complementary approaches to dissect and target these dysregulated pathways, including cell and molecular biology, RNA biochemistry and structural studies.

Importantly, we leveraged our novel findings in RNA biochemistry in the clinic, leading three pan-Canadian clinical trials, with an additional, forthcoming trial to be conducted at Northwestern University. These proof-of-principle studies demonstrated that targeting eIF4E in refractory and relapsed AML patients is efficacious, resulting in many objective responses including complete remissions. They also indicated that clinical targeting of eIF4E in AML patients with high-eIF4E led to objective clinical responses, including complete remissions in some patients where this corresponds to eIF4E targeting. These were also the first studies in humans to demonstrate that targeting eIF4E was clinically beneficial. 

Research Highlights

Clinical Trials Targeting eIF4E

  • Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber B, Roy DC, Miller WH, Borden KL. (2009). Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 114(2): 257-60.
  • Assouline, S; Gasiorek, J; Bergeron, J; Lambert, C; Culjkovic-Kraljacic, B; Cocolakis, E; Zakaria, C; Yee, K; Borden, KLB. (2023). Molecular targeting of the UDP-glucuronosyl transferase enzymes in high-eIF4E refractory/relapsed AML patients: a randomized phase II trial of vismodegib, ribavirin with or without decitabine. Haematologica. Mar 23. doi: 10.3324/haematol.2023.282791. Online ahead of print.PMID: 36951168.
  • Assouline S, Culjkovic-Kraljacic B, Bergeron J, Caplan S, Cocolakis E, Lambert C, Lau CJ, Zahreddine HA, Miller WH Jr, Borden KLB. (2015). A Phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E. Haematologica. 100(1): e7-9.

RNA Biochemistry and Cancer Biology

  • Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, Cormack G, Jaquith JB, Cerchietti L, Cocolakis E, Amri A, Bergeron J, Leber B, Becker MW, Pei S, Jordan CT, Miller WH, Borden KLB. (2014). The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 511(7507): 90-3
  • Zahreddine HA, Culjkovic-Kraljacic B, Emond A, Pettersson F, Midura R, Lauer M, del Rincon S, Cali V, Assouline S, Miller Jr WH, Hascall V, Borden KLB. (2017). The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity. eLife. 21-06-2017-ISRA: eLife-29830.
  • Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, Tabbò F, Gaudiano M, Zahreddine H, Goldstein RL, Patel J, Taldone T, Chiosis G, Ladetto M, Ghione P, Machiorlatti R, Elemento O, Inghirami G, Melnick A, Borden KLB*, Cerchietti L*, (2016). Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 127(7): 858-68.  *Co-senior author
  • Ghram, M*, Morris, G*, Culjkovic-Kraljacic, B*, Gendron, P, Skrabanek, LA, Revuelta, MV, Cerchietti, L, Guzman, ML, Borden, KLB. (2023) The eukaryotic translation initiation factor eIF4E reprogrammes the splicing machinery and drives alternative splicing. EMBO J, 2023, Apr 3;42(7):e110496. doi: 10.15252/embj.2021110496. Epub 2023 Feb 27.PMID: 36843541 (* co-first authors). 
  • Topisirovic I, Siddiqui N, Lapointe VL, Trost M, Thibault P, Bangeranye C, Piñol-Roma S, Borden KLB. (2009). Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP. EMBO journal. 28(8): 1087-98.
  • Topisirovic I, Guzman ML, McConnell MJ, Licht JD, Culjkovic B, Neering SJ, Jordan CT, Borden KLB. (2003). Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Molecular and Cellular Biology. 23(24):8992-9002.
  • Davis M, Delaleau M, Borden KLB. (2019). Nuclear eIF4E stimulates 3'-end cleavage of target RNAs through a non-canonical pathway. Cell Reports 2019 Apr 30;27(5):1397-1408.e4
  • Culjkovic-Kraljacic B, Skrabanek LA, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L, Borden KLB. (2020) The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts. Proceedings of the National Academy of Sciences USA, Oct 27;117(43):26773-26783. doi: 10.1073/pnas.2002360117. Epub 2020 Oct 14. PMID: 33055213
  • Coutinho de Oliveira L, Volpon L, Rahardjo A, Osborne MJ, Culjkovic-Kraljacic B, Trahan C, Oeffinger M, Kwok BH, Borden KLB. Structural Studies of the eIF4E-VPg complex reveal a direct competition for capped RNA: implications for translation, Proceedings of the National Academy of Sciences USA (2019); 16(48):24056-24065.
  • Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KLB. (2004). Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proceedings of the National Academy of Sciences of the United States of America. 101(52): 18105-10.
  • Kentsis A, Volpon L, Topisirovic I, Soll CE, Culjkovic B, Shao L, Borden KLB. (2005). Further evidence that ribavirin interacts with eIF4E. RNA (New York, N.Y.). 11(12): 1762-6.

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