title: A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia.
abstract: BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph(1)-ALL.
authors.affiliation: Departamento de Proliferación y Diferenciación Celular, Instituto de Microbiología Bioquímica, Universidad de Salamanca, Salamanca, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cobaleda
authors.forename: N
authors.initials: N
authors.lastname: Gutiérrez-Cianca
authors.forename: J
authors.initials: J
authors.lastname: Pérez-Losada
authors.forename: T
authors.initials: T
authors.lastname: Flores
authors.forename: R
authors.initials: R
authors.lastname: García-Sanz
authors.forename: M
authors.initials: M
authors.lastname: González
authors.forename: I
authors.initials: I
authors.lastname: Sánchez-García
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D008562:Membrane Glycoproteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009244:NAD+ Nucleosidase / Q000032:analysis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000145:classification / Q000473:pathology* / Q000637:transplantation; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D008562:Membrane Glycoproteins; D016044:Fusion Proteins, bcr-abl; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1