The mechanisms governing migration and extramedullary dissemination of leukemic cells remain obscure. In this study the migration and in vivo homing to the bone marrow of nonobese diabetic severe combined immunodeficient (NOD/ SCID) mice injected with human precursor-B acute lymphoblastic leukemia (ALL) cells in comparison to normal CD34 ؉ progenitors (both cord blood and mobilized peripheral blood) was investigated. Although migration and homing of both cell populations was dependent on stromal cell-derived factor 1 (SDF-1)/CXCR4 interactions, major differences in receptor expression as well as the migratory capacity toward various concentrations of SDF-1 were found. Furthermore, unlike normal CD34 ؉ progenitors, in vivo homing of the leukemic cells was superior when recipient NOD/SCID mice were not irradiated prior to transplantation. In addition, we report differences in the adhesion molecules activated following SDF-1 stimulation, documenting a major role for very late antigen 4 (VLA- 4 IntroductionAmong the various leukemias, B-cell precursor acute lymphoblastic leukemia (ALL) represents the most common childhood leukemia. Approximately 70% of children are cured 1 ; however, the need exists to improve the outcome in nonresponders, high-risk patients, and patients who relapse. Novel treatment strategies based on a better understanding of the biology of this type of leukemia, in particular the mechanisms that regulate migration and dissemination of the malignant clone, may assist in achieving this goal.Immune deficient severe combined immunodeficient (SCID) and nonobese diabetic (NOD)/SCID mice have been used as a functional, preclinical model for in vivo engraftment and dissemination of human pre-B ALL cells. 2,3 By using this model it was shown that the engraftment kinetics of human pre-B ALL blasts correlates with the prognosis of the disease in the original patients. [4][5][6] Stromal-derived factor-1 (SDF-1; also named CXCL12), the ligand of the CXCR4 receptor, is constitutively produced by many cell types, including immature osteoblasts and endothelial cells within the bone marrow (BM) as well as by epithelial cells in many organs, including the central nervous system. [7][8][9] Human and murine SDF-1 differ in only one amino acid and are cross-reactive. 10 SDF-1 is the most powerful chemoattractant for undifferentiated human CD34 ϩ hematopoietic progenitors 11,12 and is the only chemokine known to induce high levels of directional migration of both human CD34 ϩ /CD38 Ϫ and murine Sca-1 ϩ /ckit ϩ /Lin Ϫ stem cells. 13,14 We have previously shown the essential role of SDF-1/ CXCR4 interactions in both homing to the murine BM and high-level multilineage repopulation by human CD34 ϩ /CD38 Ϫ/low SCID repopulating cells (SRCs) in NOD/SCID mice that received transplants. 8,13,15 SDF-1, originally cloned from a stromal cell line as a pre-B cell growth factor, is essential for normal B-cell development. Mice that lack SDF-1 or CXCR4 exhibit many lethal defects, including impaired B-cell lymphopoiesis and lack o...

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