Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease

• Published in: Leukemia Vol. 19; no. 3; pp. 435 - 441
• Main Authors: EISTERER, W, JIANG, X, AUEWARAKUL, C, BARNETT, M. J, EAVES, C. J, EAVES, A. C, CHRIST, O, GLIMM, H, LEE, K. H, PANG, E, LAMBIE, K, SHAW, G, HOLYOAKE, T. L, PETZER, A. L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-03-2005; Nature Publishing Group
• Subjects: Abl protein; Animals; Autocrine signalling; BCR protein; Biological and medical sciences; CD34 antigen; CD38 antigen; Cell culture; Chromosome aberrations; Chronic myeloid leukemia; Disease Models, Animal; Fusion protein; Genotypes; Graft Survival; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte Colony-Stimulating Factor - metabolism; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - pathology; Humans; Immunodeficiency; Interleukin 3; Interleukin-3 - genetics; Interleukin-3 - metabolism; Leukemia; Leukemia, Experimental - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Myeloid leukemia; Myelopoiesis; Neoplastic Stem Cells - transplantation; Pathogenesis; Phenotype; Phenotypes; Progenitor cells; Radiation Chimera; Repopulation; Stem cell transplantation; Stem cells; Time Factors; Transplantation, Heterologous - methods; Xenografts; Xenotransplantation; British Columbia Canada; Canada; Austria; United States > US; Chromosomal aberration; Animal model; leukemia; xenografts; Stem cell; NOD/SCID mouse; Transplantation; Heterograft; Heterotransplantation; Myeloproliferative syndrome; Abnormal chromosome C9; Surgery; Chronic myelocytic leukemia; Primary; Abnormal chromosome G22; Graft; NOD/SCID mice; Hybrid gene; Chromosome translocation; Human; stem cells; CML; Hematology; Enzyme; Transferases; BCR-ABL; Malignant hemopathy; Philadelphia chromosome; Chronic; Treatment; Protein kinase; Bcr-abl protein; Abnormal chromosome
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403649

Xenograft models of chronic phase human chronic myeloid leukemia (CML) have been difficult to develop because of the persistence of normal hematopoietic stem cells in most chronic phase CML patients and the lack of methods to selectively isolate the rarer CML stem cells. To circumvent this problem, we first identified nine patients' samples in which the long-term culture-initiating cells were predominantly leukemic and then transplanted cells from these samples into sublethally irradiated NOD/SCID and NOD/SCID-beta2microglobulin-/- mice. This resulted in the consistent and durable (>5 months) repopulation of both host genotypes with similar numbers of BCR-ABL+/Ph+ cells. The regenerated leukemic cells included an initial, transient population derived from CD34+CD38+ cells as well as more sustained populations derived from CD34+CD38- progenitors, indicative of a hierarchy of transplantable leukemic cells. Analysis of the phenotypes produced revealed a reduced output of B-lineage cells, enhanced myelopoiesis with excessive production of erythroid and megakaropoietic cells and the generation of primitive (CD34+) leukemic cells displaying an autocrine IL-3 and G-CSF phenotype, all characteristics of primary CML cells. These findings demonstrate the validity of this xenograft model of chronic phase human CML, which should enable future investigation of disease pathogenesis and new approaches to therapy.