Targeted therapies in lymphoid malignancies through proteomic approaches

The main research areas of our group include:

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. Our research aims include: (a) determining whether BCAT 1/2 and BCAA metabolism are crucial for T-ALL cell proliferation and survival using T-ALL cell lines, patient-derived xenograft (PDX) samples and murine models of NOTCH1-induced leukemia; (b) Metabolomic and gene expression studies to elucidate the effects of BCAT1 loss; (c) identify regulators of BCAT1 expression in T-ALL; (d) unveil synergistic metabolic drug combinations in T-ALL models in vitro and in vivo; (e) extend our observations to other NOTCH1-dependent tumors such as chronic lymphocytic leukemia

2. Aberrant Hedgehog signaling has been described in numerous tumors. Recently, we have found that therapeutic targeting of GLI transcription factors by GANT-61 is particularly effective against NOTCH1 un-mutated T-ALL cells. Further, we have found that GLI1 contributes to T-ALL cell proliferation, survival, and dissemination through the modulation of AKT and CXCR4 signaling pathways. Our laboratory aims to identify relevant signaling pathways that regulate GLI activity and that could be implicated in modulating dexamethasone resistance in T-ALL samples.

3. Diffuse Large B-cell Lymphoma (DLBCL) represents an aggressive heterogeneous disease. The identification of prognostic factors for aggressive B-cell lymphomas still represents an un-met clinical need. Using forward phase protein arrays (FFPA), we recently identified proteins associated with overall survival (OS) from DLBCL patients. Our laboratory is pursuing the relevance of targeting the ETV6 downstream target BIRC5 and PIM2. Further, we are searching for metabolic dependencies associated with drug resistance in DLBCL.

Key Publications: 

  1. High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients. Marino D, Pizzi M, Kotova I, Schmidt R, Schröder C, Guzzardo V, Talli I, Peroni E, Finotto S, Scapinello G, Dei Tos AP, Piazza F, Trentin L, Zagonel V, Piovan E. Cancers (Basel). 2022 Jan 11;14(2):338.
  2. 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.
  1. Di Martino, L., Tosello, V., Peroni, E., and Piovan, E. (2021). Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia. International journal of molecular sciences. 14;22(16):8738.
  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.


• Principal investigator of the grants:

- “Quantificazione di biomarcatori proteici prognostici e predittivi di risposta alla terapia nei linfomi diffuse a grandi cellule B (DLBCL)” 5X1000 Fund IOV (Co-PI);

- 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”;

- Bando SID 2019 (Università degli Studi di Padova):“Using forward phase protein arrays (FPPA) to identify prognostic and drug targetable biomarkers in Diffuse Large B Cell Lymphoma (DLBCL)”;

- AIRC IG ID#22233: “Targeting non classical metabolic pathways in T-cell acute lymphoblastic leukemia”

People involved:

  • Erich Piovan RC

Other current Group members:

  • Valeria Tosello (Research Scientist, IOV), Ludovica di Martina (PhD Student)

Collaborators (local):

 Dr. Dario Marino (Clinician, IOV), Dr. Marco Pizzi (Pathologist; Department of Medicine—DIMED, University of Padova), Giorgio Arrigoni (Department of Biomedical Sciences, University of Padova)