title: Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis.
abstract: Progress in understanding the abnormal regulation of hematopoiesis in chronic myelogenous leukemia (CML) would be facilitated if neoplastic cells, at all stages of the disease, could be studied in an animal model. In this report, we show that irradiated severe combined immunodeficient (SCID) mice can be transplanted with both normal (Philadelphia chromosome [Ph]-negative) and neoplastic (Ph+) cells from CML patients with either chronic or blast phase disease. Mice transplanted with peripheral blood (PB) or bone marrow (BM) cells from 9 of 12 chronic phase CML patients were well engrafted with human cells including multilineage colony-forming progenitors and CD34+ cells for at least 90 days posttransplantation. Repeated posttransplant injections of cytokines did not enhance the number of engrafted human cells. Interestingly, approximately 70% of the human progenitors found in the engrafted SCID BM were Ph-, suggesting that the growth of primitive normal cells is favored in this in vivo transplant model. A similar number of normal cells were found in mice transplanted with either PB or BM cells, suggesting that elevated numbers of primitive normal cells are present in CML PB. When cells from patients with CML in either myeloid or lymphoid blast crisis were transplanted into SCID mice, the BM of these mice was more rapidly repopulated and to a higher level than that observed with transplants of chronic phase cells. Moreover, all human colony-forming progenitors present in the BM of mice transplanted with blast crisis cells were Ph+, and the majority of cells showed the same morphological features of the blast crisis cells originally transplanted. These experiments provide a starting point for the creation of an animal model of CML and establish the feasibility of using this model for the future characterization of transplantable CML stem cells during disease progression.
authors.affiliation: Department of Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Sirard
authors.forename: T
authors.initials: T
authors.lastname: Lapidot
authors.forename: J
authors.initials: J
authors.lastname: Vormoor
authors.forename: J D
authors.initials: JD
authors.lastname: Cashman
authors.forename: M
authors.initials: M
authors.lastname: Doedens
authors.forename: B
authors.initials: B
authors.lastname: Murdoch
authors.forename: N
authors.initials: N
authors.lastname: Jamal
authors.forename: H
authors.initials: H
authors.lastname: Messner
authors.forename: L
authors.initials: L
authors.lastname: Addey
authors.forename: M
authors.initials: M
authors.lastname: Minden
authors.forename: P
authors.initials: P
authors.lastname: Laraya
authors.forename: A
authors.initials: A
authors.lastname: Keating
authors.forename: A
authors.initials: A
authors.lastname: Eaves
authors.forename: P M
authors.initials: PM
authors.lastname: Lansdorp
authors.forename: C J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: J E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001483:Base Sequence; D001752:Blast Crisis; D001853:Bone Marrow / Q000473:pathology*; D002908:Chronic Disease; D017931:DNA Primers / Q000737:chemistry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D016313:Genes, abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011828:Radiation Chimera
chemical_list: D018941:Antigens, CD19; D018952:Antigens, CD34; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl