Research

Targeted therapies in lymphoid malignancies through proteomic approaches

The main research areas of our group include:

1. The identification, in specific leukemias and lymphomas, of the signaling cascades that function upstream of the calcineurin/NFAT signaling and the genetic and epigenetic mechanisms that drive constitutive nuclear localization of NFATs, as well as the genes that drive these malignancies.

2. The role of WT1 deletions and mutations in T-cell lymphoblastic leukemia (T-ALL) is still not clear. WT1 mutations are mainly located Exon 7 of WT1 locus and are frameshift or non-sense mutations that ultimately lead to a truncated protein which lacks the DNA binding domain located in the C-terminus of the protein. Using the shRNA and the Cripsr-Cas9 technologies we are mimicking the role of WT1 deletions and mutations in T-ALL cells. In particular, mimicking WT1 mutations in T-ALL cells will allow the identification of a de-regulated WT1 signature  and its role in the pathogenesis of T-ALL.

3. Aberrant Hh signaling has been described in numerous tumors. Recently,  Hh signaling has been shown to be activated in a subgroup of T-ALL cases, however the role of Hh signaling in the pathogenesis of T-ALL is still unclear. We aim at elucidating the mechanistic role of Hh signaling in T-ALL.

4. Diffuse Large B-cell Lymphoma (DLBCL) represents an heterogeneous disease. Retrospective analyses have shown that the ABC-subgroup has a significantly worse prognosis than the GC-B subgroup when treated with the standard R-CHOP chemotherapy. Currently, IHC based assays used to distinguish the two subgroups using routine FFPE sections have demonstrated poor reproducibility and incapacity to obtain a meaningfull stratification of patients. To try to address this issue and improve the possibility of identifying key pathways implicated in patient survival/prognosis and identify mechanisms of drug resistance, we are evaluating a novel proteomics approach based on Forward Phase Protein Arrays (FPPA) applicable to routine FFPE specimens.

Key Publications: 

1. Piovan E*., Tosello V., Amadori A. and Zanovello P*. Chemotactic Cues for NOTCH1-Dependent Leukemia. Front. Immunol., 03 April 2018  https://doi.org/10.3389/fimmu.2018.00633. Review. * Co-last authors

2. Bordin F*, Piovan E*, Masiero E, Ambesi-Impiombato A, Minuzzo S, Bertorelle R, Sacchetto V, Pilotto G, Basso G, Zanovello P, Amadori A, Tosello V. (2017). WT1 loss attenuates the TP53-induced DNA damage response in T-cell acute lymphoblastic leukemia. PMID: 29170254 DOI: 10.3324/haematol.2017.170431. * Co-first authors

3. Tosello V., Saccomani V., Yu J., Bordin F., Amadori A., Piovan E (2016). Calcineurin complex isolated from T-cell acute lymphoblastic leukemia (T-ALL) cells identifies new signaling pathways including mTOR/AKT/S6K whose inhibition synergize with Calcineurin inhibition to promote T-ALL cell death. ONCOTARGET, ISSN: 1949-2553, doi: 10.18632/oncotarget.9933 

4. Tosello V, Bordin F, Yu J, Agnusdei V, Indraccolo S, Basso G, Amadori A, Piovan E (2015). Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. LEUKEMIA, ISSN: 0887-6924, doi: 10.1038/leu.2015.335

5. Piovan E*, Yu J*, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, Sanchez-Martin M, Perez-Garcia A, Rigo I, Castillo M, Indraccolo S, Cross JR, de Stanchina E, Paietta E, Racevskis J, Rowe JM, Tallman MS, Basso G, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell. 2013 Dec 9;24(6):766-76. doi: 10.1016/j.ccr.2013.10.022. Epub 2013 Nov 27.

Funding:

• Collaborator in numerous Grants: Ricerca di Ateneo-2011-CPDA#129789 with title “Involvement of NOTCH1-regulated microRNAs and their targets in T-cell transformation”; AIRC MFAG #13053 with title-“Mechanisms of leukemogenesis induced by loss of function of WT1”  and AIRC IG#14256 with title “Role of microRNAs and their targets downstream of NOTCH1 activation in T-ALL: implications for therapeutic strategies”.

• Principal investigator of the grants: Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) Ex60% -PRAT 2015 (CPDA #152403) with titles “Targeting the Calcineurin-GSK3 axis in T-cell lymphoblastic leukemia” and “Role of constitutive calcineurin activation in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL)”. “Quantificazione di biomarcatori proteici prognostici e predittivi di risposta alla terapia nei linfomi diffuse a grandi cellule B (DLBCL)” 5X1000 Fund IOV.

People involved:
Erich Piovan RC

Faculty:
Alberto Amadori PO
Paola Zanovello PO

Other current Group members:
Valeria Tosello (Research Scientist, IOV), Deborah Bongiovanni (PhD student), Dario Marino (Clinician, IOV)