Gene expression profiling identifies ARSD as a new marker of disease progression and the sphingolipid metabolism as a potential novel metabolism in chronic lymphocytic leukemia

Article type: Research Article

Authors: Trojani, Alessandra^{a; *} | Di Camillo, Barbara^b | Tedeschi, Alessandra^a | Lodola, Milena^a | Montesano, Simona^c | Ricci, Francesca^a | Vismara, Eleonora^a | Greco, Antonino^a | Veronese, Silvio^d | Orlacchio, Aldo^c | Martino, Sabata^c | Colombo, Chiara^a | Mura, Mariangela^e | Nichelatti, Michele^f | Colosimo, Anna^d | Scarpati, Barbara^g | Montillo, Marco^a | Morra, Enrica^a

Affiliations: [a] Division of Hematology, Niguarda Hospital, Milan, Italy | [b] Department of Information~Engineering, University of Padova, Padova, Italy | [c] Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy | [d] Department of Laboratory Medicine, Molecular Pathology Unit, Niguarda Hospital, Milan, Italy | [e] Department of Laboratory medicine, Pathological Anatomy and Cytogenetics, Niguarda Hospital, Milan, Italy | [f] Service of Biostatistics, Niguarda Hospital, Milan, Italy | [g] Department of Transfusion Medicine and Division of Hematology, Niguarda Hospital, Milan, Italy

Correspondence: [*] Corresponding author: Alessandra Trojani, Department of Oncology, Division of Hematology, Niguarda Hospital, Piazza Ospedale Maggiore 3, 20162, Milan, Italy. Tel.: +39 02 64442711; Fax: +39 02 64447598; E-mail: [email protected].

Abstract: Background:Several studies demonstrated IGVH mutational status and ZAP70 expression as the most relevant prognostic markers in Chronic Lymphocytic Leukemia (CLL), suggesting the separation of two patient subgroups: with good mutated ZAP70 negative (MTZAP70-) and poor unmutated ZAP70 positive (UMZAP70+) prognosis. Design and methods:We determined the gene expression of B cells in 112 CLL patients divided into three classes: class 1 with MTZAP70-, class 2 with UMZAP70+, and class 3 included both UMZAP70- and MTZAP70+. Results:We found LPL, AGPAT2, MBOAT1, CHPT1, AGPAT4, PLD1 genes encoding enzymes involved in lipid metabolism overexpressed in UMZAP70+. In addition, this study identified ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP70+ compared to MTZAP70-. Western blots confirmed that ARSD protein levels were significantly different between the 3 classes of patients and normal controls. Statistical analysis identified a significant correlation between ARSD and IGVH; however, both ARSD protein level and IGVH were independently associated with the need for therapy of CLL patients. Conclusions:ARSD is a novel prognostic factor as the time to start therapy is shorter in patients with high levels of ARSD protein and sphingolipid metabolism could represent a new biological mechanism in CLL.

Keywords: CLL, microarray, IGVH, ARSD

DOI: 10.3233/CBM-2012-0259

Journal: Cancer Biomarkers, vol. 11, no. 1, pp. 15-28, 2012