Research

Targeted therapies in lymphoid malignancies through proteomic approaches

Main research interests:

1. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer accounting for ≈15% of pediatric and ≈25% of adult ALL cases, requiring intensive chemotherapy regimens. Gain-of function mutations in NOTCH1 are amongst the most common genetic alterations found in T-ALL. Amino acid metabolism is deregulated in numerous cancers, in particular the significance of branched chain amino acids (BCAAs) metabolism has recently emerged. In cells, BCAAs can undergo transamination through a reversible reaction, catalyzed by BCAAs transaminases (BCATs), BCAT1 present mainly in the cytoplasm and BCAT2 found in the mitochondrion.

2. Current standard-of-care treatments for T-cell acute lymphoblastic leukemia (T-ALL) include glucocorticoids, chemotherapeutics, and targeted therapies; however, relapse and resistance remain significant challenges, particularly in high-risk and early T-cell precursor (ETP) ALL subtypes. Recent research has identified ferroptosis, a regulated cell death process dependent on iron and lipid peroxidation, as a potential vulnerability in various cancers, including hematologic malignancies. Notably, resistance to standard therapies such as glucocorticoids and venetoclax has been linked to metabolic adaptations that ferroptosis induction may counteract. However, the mechanistic basis of ferroptosis regulation in T-ALL remains poorly understood. Therefore, investigating ferroptosis as a therapeutic target in T-ALL may provide novel treatment strategies, particularly for drug-resistant cases. Our research aims include: (a) characterize ferroptosis susceptibility in T-ALL subtypes; (b) identify key regulators of ferroptosis in T-ALL; (c) evaluate the therapeutic potential of ferroptosis induction.

Current research studies:

Our research aims include: (a) determining the role BCAA metabolism in T-ALL pathogenesis using T-ALL cell lines, patient-derived xenograft (PDX) samples and murine models of NOTCH1-induced leukemia through metabolomic and gene expression studies; (b) identify regulators of BCAT1 expression in T-ALL.

Ongoing Studies:

We intend to unveil synergistic metabolic drug combinations in T-ALL models in vitro and in vivo; extend our observations to other NOTCH1-dependent tumors such as chronic lymphocytic leukemia


Key Publications: 

  1. Tosello V, Di Martino L, Papathanassiu AE, Santa SD, Pizzi M, Mussolin L, Liu J, Van Vlierberghe P, Piovan E. BCAT1 is a NOTCH1 target and sustains the oncogenic function of NOTCH1. Haematologica. 2025 Feb 1;110(2):350-367.  doi:10.3324/haematol.2024.285552. PMID: 39234857; PMCID: PMC11788623.
  2. Alvarez S, da Silva Almeida AC, Albero R, Biswas M, Barreto-Galvez A, Gunning TS, Shaikh A, Aparicio T, Wendorff A, Piovan E, Van Vlierberghe P, Gygi S, Gautier J, Madireddy A, A Ferrando A. Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics, and DNA repair. Blood. 2022 Jun 9;139(23):3418-3429. doi: 10.1182/blood.2021014103. PMID: 35338774; PMCID: PMC9185155.
  1. Tosello, V., Bongiovanni, D., Liu, J., Pan, Q., Yan, K. K., Saccomani, V., Van Trimpont, M., Pizzi, M., Mazzoni, M., Dei Tos, A. P., Piovan, E. (2021b). Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination. Leukemia 35, 984-1000.
  2. Bongiovanni, D., Tosello, V., Saccomani, V., Dalla Santa, S., Amadori, A., Zanovello, P., and Piovan, E. (2020). Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia. Oncogene 39, 6544-6555.
  3. Piovan, E., Yu, J., Tosello, V., Herranz, D., Ambesi-Impiombato, A., Da Silva, A. C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., et al. (2013). Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer cell 24, 766-776.


Funding:

Principal investigator of the grants:
- Gilead Fellowship program 2018: “Differential protein expression using forward phase protein arrays to identify prognostic and drug targetable biomarkers in Diffuse Large B Cell Lymphoma”;
- AIRC IG ID#22233: “Targeting non classical metabolic pathways in T-cell acute lymphoblastic leukemia”


People involved:

Erich Piovan RC

Collaborators:

Chiara Rompietti, IOV fellow (2024); Martina Portaluri (2025), PNRR fellow; Valeria Tosello, IOV Health Researcher; Ludovica di Martino (PhD student-2024)