Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most frequentchildhood malignancy. Although it is well established that geneticabnormalities are critical for the development of ALL, the mechan-ismsthatconferaselectiveadvantagetotheleukemiacellsintheirsiteof origin, the bone marrow (BM), are largely unknown. The inter-actionsofALLblastswithBMstromalcellshaveapositiveimpactonleukemia cell survival and resistance to chemotherapy. ALL stimu-lates BM stromal cells, which reciprocally promote leukemia cellsurvival [1–7]. In addition, it is conceivable that leukemic cellspromote a microenvironmental change in the BM so as to inhibitnormal hematopoiesis.The interaction between ALL and BM stromal cells occurs inspecific cell niches, characterized by the expression of moleculessuchasE-selectinandstromal-cell-derivedfactor1(SDF-1)[8].BMniches are critical in sustaining ALL cell survival [9]. Close associ-ation of ALL to bone marrow stromal cells is important for ALLsurvivalinvitro.Adhesionisinpartmediatedbyb1integrins(VLA4and VLA5) and CD44, expressed on leukemia cells, and the fibro-nectinandvascularcelladhesionmolecule-1(VCAM-1),expressedonthestromallayer[2–4].InteractionwiththestromalVCAM-1celladhesion molecule renders VLA-4þleukemic cell lines resistant toAra-CandVP-16(etoposide)[10].BMStromalcellsproduceseveralgrowth factors [11,12]; some may provide a microenvironmentsuitable for leukemogenesis and leukemic progression. SDF-1,Interleukin-3 (IL-3), IL-7, stem cell factor (SCF), and FMS-liketyrosine kinase 3 ligand (Flt3-L) alone or in different combinationswere shown to promote the survival and or proliferation of B-cellprecursor ALL cells cultured onto BM stromal layers, although thedegreeofstimulationisheterogeneous betweenpatientsamplesandbetween growth factors [13–16]. Levels of basic fibroblast growthfactor (bFGF), hepatocytegrowth factor (HGF), and tumor necrosisfactor-a(TNF-a)aresignificantlyhigherinperipheralbloodplasmasamples frompatients withALL comparedwithhealthy controls, inassociation with increased angiogenesis [17]. The leukemic BMplasma contains increased levels of bFGF, and vascular endothelialfactor (VEGF) levels are increased in some patients [7]. Theabnormally high levels of these growth factors are able to promoteangiogenesis [7], and in some cases may directly benefit ALL cells.Forinstance,VEGFproducedbystromalcellsstimulatesBcl-2phos-phorylation and resistance of ALL cell lines to different chemo-therapeutic agents [18].