Vincenzo Ciminale.pdf

As a post-doctoral fellow at NCI, Frederick Mariland, USA I studied the expression strategies of the human oncoretroviruses HTLV-1 and HTLV-2. Over the past 20 years my studies have focused on understanding the molecular mechanisms underlying the persistence in the host and oncogenic properties of HTLVs.  Studies on the alternative splicing pattern of viral mRNAs led to the discovery of novel proteins coded by both HTLV-1 and HTLV-1 and revealed differences in their expression kinetics. To follow up on these findings, I initiated a series of studies aimed at investigating the function of some of these novel viral gene products.  My lab demonstrated that the p13 protein of HTLV-1 is targeted to the mitochondrial inner membrane where it triggers K+ influx, leading to production of reactive oxygen species (ROS).  Interestingly, in the context of in primary T-cells, these effects resulted in their ROS-dependent activation, while in leukemic T-cells p13 was pro-apoptotic. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels and that it might represent the first example of a “viral tumor suppressor”.  In the context of the HTLV-1 propagation strategy, p13 could increase the pool of “normal” infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host. Building on these findings, current studies are aimed at exploiting HTLV-1 as a model to gain insight into the general mechanisms of T-cell transformation and to develop tumor-specific therapies that exploit the higher ROS set-point of tumor cells to target pediatric T-ALL (T-acute lymphoblastic leukemia), which is not linked to a virus. As 25% of T-ALL patients respond poorly to current therapies and have a dismal prognosis, new effective therapies against these neoplasms are in high demand.

1. Silic-Benussi M, Scattolin G, Cavallari I, Minuzzo S, del Bianco P, Francescato S, Basso G, Indraccolo S, D’Agostino DM and Ciminale V. Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis. Cell Death and Disease, 2018, in press.

2. Ciccarese F, Ciminale V. Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells. Front Oncol. 2017 Jun 9; 7:117.

3. Sharova E, Grassi A, Marcer A, Ruggero K, Pinto F, Bassi P, Zanovello P, Zattoni F, D'Agostino DM, Iafrate M, Ciminale V. A circulating miRNA assay as a first-line test for prostate cancer screening. Br J Cancer. 2016 Jun 14;114(12):1362-6

4. Cavallari I, Rende F, Bona MK, Sztuba-Solinska J, Silic-Benussi M, Tognon M, LeGrice SF, Franchini G, D'Agostino DM, Ciminale V. Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence. J Virol. 2015 Nov 18;90(3):1486-98.

5. Ruggero K, Guffanti A, Corradin A, Sharma VK, De Bellis G, Corti G, Grassi A, Zanovello P, Bronte V, Ciminale V, D'Agostino DM. Small noncoding RNAs in cells transformed by human T-cell leukemia virus type 1: a role for a tRNA fragment as a primer for reverse transcriptase. J Virol. 2014 Apr;88(7):3612-22.

6. D'Agostino DM, Zanovello P, Watanabe T, and Ciminale V. (2012) The microRNA regulatory network in normal- and HTLV-1-transformed T cells. Adv Cancer Res.; 113:45-83.

7. Rende F, Cavallari I, Corradin A, Silic-Benussi M, Toulza F, Toffolo GM, Tanaka Y, Jacobson S, Taylor GP, D'Agostino DM, Bangham CR, and Ciminale V. (2011) Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNA. Blood. 117:4855-9.

8. Ruggero K, Corradin A, Zanovello P, Amadori A, Bronte V, Ciminale V, D'Agostino DM. (2010) Role of microRNAs in HTLV-1 infection and transformation. Mol Aspects Med. 31(5):367-82.

9. Silic-Benussi M, Cavallari I, Vajente N, Vidali S, Chieco-Bianchi L, Di Lisa F, Saggioro D, D’Agostino DM and Ciminale V. (2010) Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary vs. transformed cells. Blood, 116:54-62.

10. Silic-Benussi M, Biasiotto R, Andresen V, Franchini G, D'Agostino DM, and Ciminale V. (2010) HTLV-1 p13, a small protein with a busy agenda. Mol Aspects Med. 31(5):350-8.

AIRC investigator grant