Titolo: Deciphering the contribution of circular RNAs in adult Philadelphia and Philadelphia-like acute lymphoblastic leukemia

Codice Progetto: 20222EC7LA

Responsabile scientifico per il DMM: Prof.ssa Stefania Bortoluzzi
Coordinatore: Università degli Studi di ROMA "La Sapienza" - Prof.ssa Sabina CHIARETTI

Partner-Unità di ricerca: Università degli Studi di PADOVA

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 255.810,00 - CUP C53D23002160006

Abstract del progetto

In this project, we will evaluate the role of circular RNAs (circRNAs) in leukemogenesis of 2 acute lymphoblastic leukemia (ALL) subsets, Philadelphia (Ph+) and Philadelphia-like (Ph-like) ALL. CircRNAs, a pleiotropic class of RNAs that regulate cellular processes and control key oncogenic axes, are still unexplored in Ph+ and Ph-like ALL, thus representing promising candidates to discover new disease mechanisms and prognostic markers possibly leading to more targeted treatments. Though the management of Ph+ ALL improved in the last 20 years, some patients will still relapse, either with or without the known poor outcome-associated factors, ABL1 mutations and IKZF1plus signature. Therefore, we seek to identify circRNAs involved in the biological processes responsible for Ph+ ALL relapse to current approaches (Figure 1). Moreover, circRNAs associated with Ph+ ALL could refine the prognostic algorithms defining allogeneic transplant allocation. About 20% of B-lineage ALL are Ph-like, i.e. displaying a transcriptional profile similar to that of Ph+ ALL but lacking the BCR-ABL1 transcript characterized by a poor outcome and a heterogeneous genetic landscape. Presently, a standardized model identifying these cases is missing. We will compare Ph-like and Ph- ALL circRNAomes to detect circRNA expression specific to Ph-like cases, including those lacking known rearrangements. By determining a Ph-like circRNA signature, we could improve diagnostic and prognostic tools and possibly uncover circRNAs with therapeutic implications. Next, we will compare circRNAomes of Ph-like with Ph+ cases, foreseeing a great degree of similarity (Figure 1). We devised a comprehensive transcriptomic study of 60 B-ALL cases to answer two questions. First, comparison of 30 newly-diagnosed Ph+ ALL adult patients, 20 who experienced disease recurrence and 10 who did not, will allow identifying circRNAs involved in relapse. Second, given the heterogeneity of Ph-like ALL, we will compare 20 Ph-like samples focusing mainly, but not exclusively, on patients devoid of rearrangements involving kinases. Ten additional B-lineage ALL samples with no major molecular lesions will be included for comparison. We will use ribodepleted RNA-seq to study linear and circular RNAs, leveraging advanced bioinformatics methods. A validation on a large set of samples is planned. The project will be carried out jointly by two research groups with prominent expertise in ALL clinics and translational research, molecular diagnosis, circRNA bioinformatics, and circRNA hematological studies. The PI collaborates with the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) leading ALL clinical trials nationwide for Ph+ ALL and a soon to open trial for Ph-like ALL. Access to the GIMEMA biological banking is thus warranted. This innovative project opens the possibility to identify novel diagnostic and prognostic markers and therapeutic targets for Ph+ and Ph-like ALL.