Increased CCL2 and IL-8 in the Bone Marrow Microenvironment in Acute Lymphoblastic Leukemia

Background. the interactions of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival. in the present study, we proposed to identify and investigate the role of molecules critically involved in leukemia-microenvironment crosstalk. Procedure. Gene expression profiling analyses of BM mesenchymal stem cells (BMMSC) were performed following stimulation by ALL cells. CCL2 and IL-8 plasma levels were evaluated from, ALL patients and controls. Expression of the CCL2 and IL-8 receptors in ALL was determined by RT-PCR. the biological effects of CCL2, IL-8 or its neutralizing antibodies in primary precursor-B ALL and BMMSC cells were evaluated using in vitro assays. Results. Leukemia stimulation of BMMSC upregulated the expression of several inflammatory chemokines, including CCL2 and IL-8. the BM plasma levels of CCL2 and IL-8 in children at diagnosis were significantly higher than in healthy controls (P < 0.00)). Functional studies revealed that CCL2 and IL-8 enhanced the capacity of BMMSC to support adhesion of ALL cells. CCL2 and IL-8 were also found to enhance BMMSC survival and to increase their proliferation. ALL cells were not directly affected by CCL2 or IL-8. Conclusions. the leukemic BM microenvironment had increased levels of CCL2 and IL-8. These chemokines are known to have suppressive effects in normal hematopoiesis. Our data indicate that CCL2 and IL-8 have a positive impact on BMMSC survival, proliferation, and adhesiveness to ALL cells. Leukemia-associated CCL2 and IL-8 upregulation may represent one possible mechanism of microenvironment perversion in favor of ALL cells. Pediatr Blood Cancer 2011;56:568-577. (C) 2010 Wiley-Liss, Inc.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Ctr Infantil Boldrini, Lab Biol Mol, BR-13083210 Campinas, SP, BrazilUniv Estadual Campinas, Fac Med Sci, Dept Med Genet, Campinas, SP, BrazilCtr Struct Mol Biol, Brazilian Synchrotron Light Lab, Campinas, SP, BrazilIndiana Univ Sch Med, IU Simon Canc Ctr, Indianapolis, in USAUniv Estadual Campinas, Fac Med Sci, Dept Pediat, Campinas, SP, BrazilFAPESP: 05/02390-4FAPESP: 06/02083-7FAPESP: 06/01158-3FAPESP: 08/02106-2CNPq: 401122/05CNPq: 382.687/2008-6Web of Scienc