title: A comparison of the effect of bcr/abl breakpoint specific phosphothiorate oligodeoxynucleotides on colony formation by bcr/abl positive and negative, CD34 enriched mononuclear cell populations.
abstract: In chronic myeloid leukaemia, the expression by clonal cells, of a leukaemia specific bcr/abl chimeric mRNA, makes the condition suitable for the application of "antisense" strategies. Furthermore, the origin of the condition in a pluripotential progenitor allows enrichment of leukaemic clonogenic cells by selection for CD34 expression, together with a useful reduction in contaminating accessory cells. In a methylcellulose clonogenic assay system we incubated bcr/abl expressing (n = 9) and bcr/abl negative (n = 8), CD34 enriched progenitors with phosphothiorate oligodeoxynucleotides (PS oligomers), antisense and sense to the b3a2 and b2a2 chimeric bcr/abl junctional sequences. All samples were cloned in the presence of both antisense, and sense PS oligomers to provide appropriate controls. For bcr/abl positive progenitors, the mean number of colonies formed was reduced by 21 (39%) (P < 0.05) in the presence of the specific antisense oligomer, 11 (20%) (P < 0.05) with the antisense oligomer directed to the alternative junctional breakpoint, and colony formation was not significantly altered by either sense PS oligomer. Colony formation by bcr/abl negative progenitors was not reproducibly reduced by any of the PS oligomers. These results confirm that PS oligomers can have a sequence dependent inhibitory effect on a CD34 enriched progenitor population from patients with chronic myeloid leukaemia.
authors.affiliation: Department of Clinical Haematology, Manchester Royal Infirmaty, U.M.I.S.T., U.K.
authors.forename: R
authors.initials: R
authors.lastname: Chasty
authors.forename: A
authors.initials: A
authors.lastname: Whetton
authors.forename: G
authors.initials: G
authors.lastname: Lucas
mesh_terms: D018952:Antigens, CD34 / Q000494:pharmacology*; D001483:Base Sequence; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000187:drug effects; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012016:Reference Values; D013873:Thionucleotides / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D016044:Fusion Proteins, bcr-abl