Prof. Vincenzo Ciminale, MD
Over the last two decades, Vincenzo Ciminale has investigated the mechanisms of T-cell transformation using the leukemogenic retrovirus HTLV-1 (human T-cell leukemia virus type 1) as a model. His studies of the coding potential of HTLV-1 and a related non-pathogenic virus named HTLV-2 led to the discovery of several novel regulatory proteins produced from alternatively spliced mRNAs (J. Virol. 1992; Virology, 1995; J. Virol., 1997). Investigations of the function of p13, one of the newly identified proteins of HTLV-1, showed that this protein is targeted to mitochondrial and induce fission of these organelles (Oncogene, 1999), increases mitochondrial permeability to K+ (J. Biol. Chem., 2002) which leads to a tumor-suppressor function (Proc. Natl. Acad. Sci., 2004), sensitization to death of tumor cells (Cell Death Diff., 2005), and increased production of reactive oxygen species (ROS) (Blood, 2010; Mol. Asp. Med. 2010). We also provided evidence for a temporal pattern of HTLV-1 expression and revealed major differences in the intracellular compartmentalization of HTLV-1 transcripts (Blood, 2011) and a role for small non-coding RNAs in HTLV-1 infection (Mol. Asp. Med. 2010; J. Virol., 2014). In addition, a new research line led to the development of a circulating microRNAs assay as a first-line test for prostate cancer screening (Brit. J. Cancer, 2016).
In a more recent study, we have provided proof-of-concept evidence for an integrated pharmacological approach to target refractory T-ALL based on the rewiring of their redox homeostasis (Silic-Benussi et al. , 2018).
Harnessing redox homeostasis and cell death pathways for treatment of T-cell leukemia
Investigations into the role of mitochondria and redox homeostasis in the mechanisms of T-cell transformation, will provide leads for the development of innovative therapies for treating T-cell leukemias.
Mitochondria, cancer cell metabolism, reactive oxygen species, leukemia.
Intracellular reactive oxygen species (ROS) constitute a homeostatic “rheostat” whose perturbation can lead to cell death. Cancer cells generally have increased ROS levels compared to normal cells. According to the ROS rheostat model, a further increase in ROS could engage death pathways in cancer cells while sparing normal cells, which have a lower ROS set-point. In line with this hypothesis, our previous studies revealed that HTLV-1, the causative agent of adult T-cell leukemia (ATL), codes for p13, a mitochondrial protein that increases mitochondrial ROS production and sensitizes transformed T-cells to death signals without harming normal T-cells. Based on these findings, we have set out to investigate ROS homeostasis in acute T-lymphoblastic leukemia (T- ALL) and devise ROS-based strategies to kill transformed cells.
We are testing drugs that increase mitochondrial ROS production with strategies to block scavenging pathways whose activity might otherwise blunt the efficacy of ROS- inducers. Treatments are tested in vitro on T-ALL cell lines and short-term cultures of primary T- ALL xenografts. We are characterizing the ROS set-point of the T-ALL leukemia-initiating cell (LIC) subpopulation to test whether ROS modulators might deplete their self-renewal capacity. ROS-enhancing treatments are combined with drugs that engage cell death pathways (e.g. TRAIL). Effective treatments will tested in vivo in mice inoculated with HTLV-1-transformed cells and T-ALL xenografts.
Conclusions and perspectives
Approximately 25% of T-ALL have a dismal prognosis as these patients are refractory to current therapies; our studies will provide leads for the development of innovative therapies for treating patients with refractory T-ALL.
- Donna D’Agostino
- Ilaria Cavallari
- Micol Silic-Benussi
- Francesco Ciccarese
- Gloria Scattolin
- Vittoria Raimondi
- Evgeniya Sharova
- 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, 114:1362-6.
- 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, 90:1486-98.
- 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, 88:3612-22.