Dr. Valeria Tosello, Biologist
From 2000-2006, Valeria Tosello has been involved in several project focused on tumor immunology first in the laboratory of Prof. Alberto Amadori and Prof. Paola Zanovello at the University of Padova and subsequently, in the laboratory of Prof. Danila Valmori at Columbia University in New York City. She has worked on several interesting topics in the tumor immunology field such as studying the role of IFNa on dendritic cell differentiantion and antigen presentation (Tosello V., Eur J Immunol. 2009, Jan) and the characterization of naïve and memory T-regulatory cells (Tosello V., Clin Immunol. 2008 Mar).
On 2006, she subsequently moved in the laboratory of Adolfo Ferrando, at the Institute for Cancer Genetics at Columbia University, where she developed a strong background on the cellular and molecular biology of T-cell acute lymphoblastic leukemia (T-ALL). She contributed to several works centered on drug resistance and targeted therapies, with particular respect to NOTCH1 signaling (Sulis ML., Blood. 2008 Aug; Real Pj, Nat Med. 2009 Jan; Herranz D., Nat Med. 2015 Oct). She identified somatic mutations in WT1 tumor suppressor gene in T-ALL (Tosello V., Blood. 2009 Jul). She is still involved on studies focused on the role of WT1 tumor suppressor gene in acute myeloid leukemia (AML) (Rampal R., Cell Rep. 2014 Dec) and T-ALL. Her research interest is focused on altered signaling pathway on T-ALL which involves Calcineurin activation (Tosello V., Oncotarget 2016, June; Tosello V., Leukemia 2016 April) and de-regulated microRNAs.
Molecular pathogenesis of T-cell acute lymphoblastic leukaemia and lymphoma
A comprehensive understanding of role of the molecular mechanisms involved in the pathogenesis of T-ALL will open new possibilities of targeted therapeutic interventions.
De-regulated signaling pathways in T-leukemia/lymhoma, mechanisms of resistance and relapse.
T-lineage acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of pediatric and 25% of adult ALL cases. The introduction of intensive combination chemotherapy protocols has led to remarkable improvements in survival for this disease; however, in contrast with the favorable response to therapy in patients at diagnosis, the prognosis of T-ALL patients with relapsed leukemia remains poor, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective antileukemic drugs. Our research interest focuses particularly on those alterations which result still poorly understood.
- The role of WT1 deletions and mutations in 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.
- NOTCH1 pathway results mutated in over 60% of cases of T-ALL cases, making NOTCH1 oncogene an appealing molecular target in T-ALL. In the last years, different attempts to target NOTCH signaling in T-ALL have been developed: the administration of GSI, which block cleavage of NOTCH receptors and the use of anti-NOTCH1 antibodies that more specifically target T-ALL cells carrying NOTCH1 activation. In this scenario, the understanding of the molecular mechanisms downstream of NOTCH1 signaling is fundamental to design novel therapeutic strategies. The role microRNAs downstream NOTCH1 signaling have been recently explored, however their role is not completely clear. Our laboratory is currently studying novel microRNAs downstream NOTCH1 and their roles in T-ALL pathogenesis.
- The diagnosis of lymphoid malignancy remain challenging in about 10% of lymphoproliferative disorders and clonality tests are often requested to confirm diagnostic hypotheses. Currently, the goal standard method to analyze clonaltity for clinical molecular diagnostic is based in PCR-based approaches. Our laboratory is currently implementing this analysis with next generation sequencing approaches. This analysis will allow the identification of clonality at diagnosis with a more quantitative a sensitive approach and the eventual re-emergence of these clones after the treatment.
Conclusions and perspectives
Approximately 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective anti-leukemic drugs. The better understanding of the mechanistic role of each of alterations will help the design of new targeted combination therapies incorporating specific inhibitors to conventional anti-leukemic drugs.
- Erich Piovan (co-leader)
- Valentina Saccomani
- Deborah Bongiovanni
Selected references (last 3 years)
- Tosello V, Saccomani V, Yu J, Bordin F, Amadori A, Piovan E. 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. 2016 Jun 10. doi: 10.18632/oncotarget.9933.
- Tosello V, Bordin F, Yu J, Agnusdei V, Indraccolo S, Basso G, Amadori A, Piovan E. Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. Leukemia. 2016 Apr;30(4):812-22. doi: 10.1038/leu.2015.335.
- Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, Márquez J, Matés JM, Kung AL, Rayport S, Cordon-Cardo C, DeBerardinis RJ, Ferrando AA. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med. 2015 Oct;21(10):1182-9. doi: 10.1038/nm.3955.