Engraftment of Acute Myeloid Leukemia in NOD/SCID Mice Is Independent of CXCR4 and Predicts Poor Patient Survival

The aim of this study was to investigate factors influencing the engraftment potential of acute myeloid leukemia (AML) CD34+ cells in nonobese diabetic/ severe combined immunodeficiency (NOD/SCID) mice. We examined the relationship between engraftment, CXCR4 expression on CD34+ and CD34+CD38− cells, and patient (Pt) clinical/laboratory characteristics in 44 samples from 11 Pts. Engraftment, evaluated by Southern blot and CD45 flow cytometric analyses, was observed in murine bone marrow of 6 of 11 Pt samples, ranging from 0.1% to 73.9% by Southern blot and from 0.1%‐36.8% by flow cytometry. Poor Pt prognosis was inversely correlated with engraftment; the median overall survival was 95.9 weeks for Pts whose cells did not engraft and 26.1 weeks for those whose cells did engraft (p = 0.012, log‐rank test). No other clinical/laboratory variable predicted engraftment. No correlation between the level of CXCR4 expression on AML cells and engraftment was observed. Cells with virtually absent CXCR4 expression were able to engraft, and cells from two Pts with high expression levels of CXCR4 did not engraft. Furthermore, anti‐CXCR4 antibody failed to block the engraftment of AML cells into NOD/SCID mice. In conclusion, we demonstrated that CXCR4 is not critical for the engraftment of AML CD34+ cells in NOD/SCID mice. The model may, however, reflect the clinical course of the disease.

[1]  M. Wasik,et al.  Biological significance of the expression of HIV-related chemokine coreceptors (CCR5 and CXCR4) and their ligands by human hematopoietic cell lines , 2000, Leukemia.

[2]  B. Löwenberg,et al.  Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene , 2000, Leukemia.

[3]  J. Dürig,et al.  Differential expression of chemokine receptors in B cell malignancies , 2001, Leukemia.

[4]  L. Bendall,et al.  Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms. , 1993, Blood.

[5]  J. Belmont,et al.  BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model , 2001, Oncogene.

[6]  L. Ailles,et al.  Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. , 1999, Blood.

[7]  H. W. Lee,et al.  Dissociation between stem cell phenotype and NOD/SCID repopulating activity in human peripheral blood CD34(+) cells after ex vivo expansion. , 2001, Experimental hematology.

[8]  J. Dick,et al.  A newly discovered class of human hematopoietic cells with SCID-repopulating activity , 1998, Nature Medicine.

[9]  L. Kanz,et al.  Functional response of leukaemic blasts to stromal cell‐derived factor‐1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia , 2000, British journal of haematology.

[10]  A. Martens,et al.  Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model , 2000, Leukemia.

[11]  A. Nagler,et al.  Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice. , 2001, Blood.

[12]  R. Alon,et al.  The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow. , 1999, The Journal of clinical investigation.

[13]  David A. Williams,et al.  Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse as a model system to study the engraftment and mobilization of human peripheral blood stem cells. , 1998, Blood.

[14]  O. Kollet,et al.  Immune-deficient SCID and NOD/SCID mice models as functional assays for studying normal and malignant human hematopoiesis , 1997, Journal of Molecular Medicine.

[15]  David A. Williams,et al.  Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy , 1996, Nature Medicine.

[16]  D. Greiner,et al.  Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. , 1995, Journal of immunology.

[17]  G Mann,et al.  High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia , 2001, British journal of haematology.

[18]  R. Alon,et al.  The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. , 2000, Blood.

[19]  L. Kanz,et al.  Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1) , 1999, Leukemia.

[20]  C. Eaves,et al.  Human growth factor-enhanced regeneration of transplantable human hematopoietic stem cells in nonobese diabetic/severe combined immunodeficient mice. , 1999, Blood.

[21]  A. Nagler,et al.  Human CD34(+)CXCR4(-) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation. , 2002, Blood.

[22]  P. Thall,et al.  Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. , 2001, Blood.

[23]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[24]  D. Hogge,et al.  Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(-)/HLA-DR-. , 1998, Blood.

[25]  T. Kipps,et al.  Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. , 2000 .

[26]  P. Lansdorp,et al.  Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. , 1997, Blood.

[27]  J. Sodroski,et al.  The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry , 1996, Nature.

[28]  Kouji Matsushima,et al.  The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract , 1998, Nature.

[29]  D. Kelvin,et al.  The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Liesveld,et al.  Expression of integrins and examination of their adhesive function in normal and leukemic hematopoietic cells. , 1993, Blood.

[31]  S. Nishikawa,et al.  Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 , 1996, Nature.

[32]  J. Dick,et al.  Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice , 1999, Bone Marrow Transplantation.

[33]  P. Meltzer,et al.  Human AML cells in NOD/SCID mice: engraftment potential and gene expression , 2002, Leukemia.

[34]  M Keeney,et al.  Characterization of Chemokine Receptors Expressed in Primitive Blood Cells During Human Hematopoietic Ontogeny , 2000, Stem cells.

[35]  S. Rafii,et al.  The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. , 1998, Blood.

[36]  L. Ailles,et al.  Retroviral marking of acute myelogenous leukemia progenitors that initiate long-term culture and growth in immunodeficient mice. , 1999, Experimental hematology.

[37]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[39]  G. Spangrude,et al.  Marrow engraftment of hematopoietic stem and progenitor cells is independent of Galphai-coupled chemokine receptors. , 1999, Experimental hematology.

[40]  N Tsukada,et al.  Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. , 2000, Blood.