How the microenvironment shapes chronic lymphocytic leukemia: the cytoskeleton connection CRISTINA SCIELZO 1,4 , ELISA TENHACKEN 1 , MARIA T. S. BERTILACCIO 1 , MARTA MUZIO 1 , CARLO CALISSANO 1,2 , PAOLO GHIA 1,2,3 , & FEDERICO CALIGARIS-CAPPIO 1,2,3 1 Uni tof Lymphoi d Ma l i gnanci es, D i v i si on of M ol ecul ar Oncology, I st i t uto Sci ent i fico San Ra ff a el e , M i l an, I t a l y, 2 C l i ni c a l Uni tof Lymphoi d Ma l i gnanci es, D epartmentof Oncology, I st i t uto Sci ent i fico San Ra ff a el e , M i l an, I t a l y, 3 Uni v ersi t a ` V i t a- Sa l ut e San Ra ff a el e , M i l an, I t a l y, and 4 Uni v ersi t a ` degl i St udi di M i l ano, M i l an, I t a l y Abstract Chronic lymphocytic leukemia (CLL) is characterized by the accumulation in primary and secondary lymphoid tissues of CD5 þ B cells that have the same B cell receptor (BCR) rearrangement. Genetic alterations and different stimuli originating from the microenvironment cooperate in the selection and expansion of the malignant clone. Molecular and functional analyses suggest that stimulation through the BCR affects the destiny of leukemic cells in terms of life or death. Microenvironmental signals arecrucial for this process, inducing proliferation and leading to the survival and accumulation of leukemic cells within lymphoid organs. Nevertheless, a number of major biologicalissues still remain to be solved, including the relationships between cell proliferation and cell accumulation within lymphoid organs as well as the mechanisms that regulate CLL cell migration and recirculation between peripheral blood and lymphoid tissues. We focused on the role played by thecytoskeleton, given its relevance in controlling cellular shape, mobility, and homing. We hypothesize that hematopoietic cell-specific Lyn substrate 1 (HS1), a putative prognostic marker in CLL that interacts with distinct cytoskeleton adapters in leukemic B-lymphocytes, could regulate the CLL cell cytoskeleton. Keywords: CLL , M i croenv i roment , Cytos k el eton Background Several studies indicate thatthe microenvironment has a critical role in chronic lymphocytic leukemia (CLL) cell survival and accumulation, suggesting that it may have a fundamentalinfluence on clonal evolution [1]. Circulating CLL cells are largely arrested in the G 0 /G 1 phase of the cell cycle, but a small proportion of leukemic lymphocytes accumulate in the so-called ‘proliferation centers’ (PCs) in the lymph nodes and the bone marrow (BM), where signals delivered from the microenvironment are likely crucialin inducing proliferation of leukemic cells [2,3]. Furthermore, in the PCs, leukemic lymphocytes are in contact with numerous CD4 þ T cells that express CD40 ligand (CD40L) and can supportthe growth of CLL cells through CD40 ligation. The hypothesis can also be raised that antigen (in particular auto-antigen) stimulation may be another triggering event that induces leukemic cell activation and cell cycleentry in the PCs. In v i t ro (and likely i nv i vo), CLL cell apoptosis can be rescued by the presence of stromal cells and nurse-like cells [4,5]. It is also possible that the interaction between CD38 on the surface of CLL cells and its ligand CD31 may play a role [6]. Indeed, the use of deuterium to label proliferating cells i nv i vo has revealed that, within each clone, CD38 þ cells proliferate 2.5 times faster than CD38 7 cells [7]. In the same study, a relationship between i n v i vo kinetics, levels of expression of CXCR4, and clinical outcome was suggested. Cytokines such as inter- leukin-4 (IL-4), and chemokines such as CXCL12 (stromal cell-derived factor-1 [SDF-1], CXCR4 Correspondence: Dott. Cristina Scielzo, Unit of Lymphoid Malignancies, Division of Molecular Oncology, Istituto Scientifico San Raffaele, Via Olgettina 58, 20133, Milano, Italy. E-mail: scielzo.cristina@hsr.it L euk emi a & Lymphoma , August 2010; 51(8): 1371–1374 ISSN 1042-8194 print/ISSN 1029-2403 online 2010 Informa UK, Ltd. DOI: 10.3109/10428194.2010.505061 Leuk Lymphoma Downloaded from informahealthcare.com by Ospedale San Raffaele on 08/05/10 For personal use only.