RNA-based therapies by microRNA restoration and circular RNA targeting for T-cell chronic lymphoproliferative disorders

PI:

Stefania Bortoluzzi

Email:

stefania.bortoluzzi@unipd.it

Affiliation:

Complete name of the Institution and link to the web site of the Institution University of Padova

ORCID:

0000-0001-8240-3070

T large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disease whose pathogenesis is still not completely understood and lacking a curative therapy. We contributed to the definition of the genetic bases of T-LGLL and recently described the transcriptome aberrancies in this malignancy, collecting relevant preliminary data about the dysregulation of circular RNAs (circRNAs) in leukemia cells.

CircRNAs, stable transcripts generated by backsplicing, are versatile regulators of biological processes, control oncogenic axes and are nowadays regarded as very interesting molecules to be explored as biomarkers and, particularly, for their involvement in disease mechanisms, their potential as new therapeutic targets, or therapeutic molecules themselves.

Our group has valuable experience on circRNA molecular biology and bioinformatics and we recently provided new evidence about circRNA roles in acute leukemias. 

In this project, by omics and functional studies, we will disclose and validate circRNA dysregulation in T-LGLL. Next, we will leverage circRNAs by silencing experiments in-vitro, to study their involvement in relevant disease mechanisms as a prerequisite for the development of circRNA targeting therapies. 

Innovative bioinformatics methods to characterize circRNAs are expected as a valuable by-product of this project, and broader applications, in other malignancies, for circRNA-based therapies strategies are also envisaged. 

Selected publication (2023)

  • Vromman M, Anckaert J, Bortoluzzi S, Buratin A, Chen CY, Chu Q, Chuang TJ, Dehghannasiri R, Dieterich C, Dong X, Flicek P, Gaffo E, Gu W, He C, Hoffmann S, Izuogu O, Jackson MS, Jakobi T, Lai EC, Nuytens J, Salzman J, Santibanez-Koref M, Stadler P, Thas O, Vanden Eynde E, Verniers K, Wen G, Westholm J, Yang L, Ye CY, Yigit N, Yuan GH, Zhang J, Zhao F, Vandesompele J, Volders PJ. Large-scale benchmarking of circRNA detection tools reveals large differences in sensitivity but not in precision. NAT METHODS. 2023 Aug;20(8):1159-1169. doi: 10.1038/s41592-023-01944-6. COVER PAGE (August 2023 issue of NATURE METHODS: https://www.nature.com/nmeth/volumes/20/issues/8).
  • Buratin A, Borin C, Tretti Parenzan C, Dal Molin A, Orsi S, Binatti A, Simon K, Paganin M, Serafin V, Gaffo E, Te Kronnie G, Van Vlierberghe P, Bresolin S, Bortoluzzi S.  CircFBXW7 in patients with T-cell ALL: depletion sustains MYC and NOTCH activation and leukemia cell viability. EXP HEMATOL ONCOL. 2023 Jan 21;12(1):12. doi: 10.1186/s40164-023-00374-6.
  • Buratin A, Bortoluzzi S, Gaffo E.  Systematic benchmarking of statistical methods to assess differential expression of circular RNAs. BRIEF BIOINFORM. 2023 Jan 19;24(1):bbac612. doi: 10.1093/bib/bbac612.
  • Dal Molin A, Tretti Parenzan C, Gaffo E, Borin C, Boldrin E, Meyer LH, Te Kronnie G, Bresolin S, Bortoluzzi S.  Discovery of fusion circular RNAs in leukemia with KMT2A::AFF1 rearrangements by the new software CircFusion. BRIEF BIOINFORM. 2023 Jan 19;24(1):bbac589. doi: 10.1093/bib/bbac589.
  • Semenzato G, Calabretto G, Barilà G, Gasparini VR, Teramo A, Zambello R. Not all LGL leukemias are created equal. BLOOD REV. 2023 Feb 20:101058.
  • Barilà G, Grassi A, Cheon H, Teramo A, Calabretto G, Chahal J, Vicenzetto C, Almeida J, Shemo BC, Shi M, Gasparini VR, Munoz-Garcia N, Pastoret C, Nakazawa H, Oshimi K, Sokol L, Ishida F, Lamy T, Orfao A, Morice WG, Loughran TP, Semenzato G, Zambello R. Tγδ LGLL identifies a subset with more symptomatic disease: analysis of an international cohort of 137 patients. BLOOD. 2023 Mar 2;141(9):1036-1046.
  • Vicenzetto C, Gasparini VR, Barilà G, Semenzato G, Teramo A, Calabretto G, Rampazzo E, Carraro S, Trimarco V, Trentin L, Facco M, Semenzato G, Zambello R. Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia. HAEMATOLOGICA. 2023 Jul 13. Online ahead of print. doi: 10.3324/haematol.2022.282306. 

Selected publication (2022)

  • Buratin A, Romualdi C, Bortoluzzi S, Gaffo E. Detecting differentially expressed circular RNAs from multiple quantification methods using a generalized linear mixed model. COMPUT STRUCT BIOTECHNOL J. 2022 May 20;20:2495-2502. doi: 10.1016/j.csbj.2022.05.026. 
  • Dal Molin A, Gaffo E, Difilippo V, Buratin A, Tretti Parenzan C, Bresolin S, Bortoluzzi S. CRAFT: a bioinformatics software for custom prediction of circular RNA functions. BRIEF BIOINFORM. 2022 Mar 10;23(2):bbab601. doi: 10.1093/bib/bbab601. PMID: 35106564 Free PMC article.
  • Gaffo E, Buratin A, Dal Molin A, Bortoluzzi S. Sensitive, reliable and robust circRNA detection from RNA-seq with CirComPara2. BRIEF BIOINFORM. 2022 Jan 17;23(1):bbab418. doi: 10.1093/bib/bbab418.
  • Teramo A, Binatti A, Ciabatti E, Schiavoni G, Tarrini G, Barilà G, Calabretto G, Vicenzetto C, Gasparini VR, Facco M, Petrini I, Grossi R, Pisanti N, Bortoluzzi S, Falini B, Tiacci E, Galimberti S, Semenzato G, Zambello R.  Defining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation. Nat Commun. 2022 Jun 8;13(1):3298. doi: 10.1038/s41467-022-31015-x.
Facebook
Twitter
LinkedIn

Related Projects

PI: Pierpaolo Ceci