Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models

// Mimma Bianco 1 , Anna Gasparri 1 , Luca Generoso 1 , Emma Assi 1 , Barbara Colombo 1 , Lydia Scarfo 2, 3, 4 , Maria T.S. Bertilaccio 5 , Cristina Scielzo 5 , Pamela Ranghetti 5 , Eleonora Dondossola 1 , Maurilio Ponzoni 3 , Federico Caligaris-Cappio 3, 4, 5 , Paolo Ghia 2, 3, 4 , Angelo Corti 1, 4 1 Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy 2 B Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy 3 Clinical Lymphoma Unit, Department of Onco-Hematology, San Raffaele Hospital, Milan 20132, Italy 4 San Raffaele Vita-Salute University, Milan 20132, Italy 5 Lymphoid Malignancies Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy Correspondence to: Angelo Corti, email: corti.angelo@hsr.it Keywords: chromogranin A, vasostatin-1, chronic lymphocytic leukemia, tumor cell trafficking, endothelial barrier function Received: February 16, 2016 Accepted: April 26, 2016 Published: May 17, 2016 ABSTRACT Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA 1-76 ), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA 1-439 (0.3 μg, i.v., or 1.5 μg/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Eμ-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2 −/− γc −/− mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro , CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA 1-373 ), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.