Inhibition of in vitro proliferation of chronic myelogenous leukemia progenitor cells by c-myb antisense oligodeoxynucleotides.
Normal hematopoietic progenitors and acute myelogenous leukemia cells show a differential requirement for the encoded product of c-myb proto-oncogene for proliferation. To determine whether c-myb is also differentially required for the proliferation of hematopoietic progenitors of chronic myelogenous leukemia (CML), mononuclear cells derived from both chronic phase and blast crisis were exposed to c-myb antisense oligodeoxynucleotides and assayed for colony-forming ability. Exposure of CML-BC cells from 12 patients to c-myb antisense oligodeoxynucleotides resulted in significant (p<001) inhibition of leukemia colony formation (average inhibition 63%) and was accompanied by down-regulation of c-myb expression. Colonies derived from CML chronic phase progenitors were virtually unaffected in 10 cases, but down-regulation of c-myb expression was not detected. However, in studies conducted with CD34+ leukemia cells, a subset highly enriched for hematopoietic progenitors, colony formation was inhibited at both disease stages, whereas CFU-GM colony formation derived from normal CD34+ cells was not affected by exposure to c-myb antisense oligodeoxynucleotides. These data suggest that CML chronic phase and blast crisis progenitors are both sensitive to the inhibitory effects of c-myb antisense oligomers, and that the lack of inhibition in partially purified CML-chronic phase progenitors is probably due to inefficient penetration of oligodeoxynucleotides into the clonogenic cells. The preferential effect of c-myb antisense oligodeoxynucleotides on colonies arising from the compartment that includes CML-CD34+ progenitors likely reflects the expansion of a cell population with high proliferative potential and elevated c-myb mRNA levels.
Szczylik
C
C
Department of Oncology, CSK WAM, Warszawa, Poland.
Skórski
T
T
Malaguarnera
L
L
Hetman
J
J
Chen
S T
ST
Calabretta
B
B
D018952:Antigens, CD34 / Q000096:biosynthesis; D001752:Blast Crisis / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020598:Proto-Oncogene Proteins c-myb; D013234:Stem Cells / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000096:biosynthesis
D018952:Antigens, CD34; D017931:DNA Primers; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D001613:beta 2-Microglobulin; D011505:Protein-Tyrosine Kinases; D013936:Thymidine