Normal and leukemia hematopoietic cells manifest differential sensitivity to inhibitory effects of c-myb antisense oligodeoxynucleotides: An in vitro study with relevance to bone marrow purging

The c-myb protooncogene is preferentiallyexpressed in hematopoietic cells, and its encoded protein, Myb,is required for hematopoietic cell proliferation. To analyze therelative Myb dependence of normal and leukemic humanhematopoietic progenitor cells, normal bone marrow cells,several types ofleukemic blast cells, and 1:1 mixtures of normaland leukemic cells were cultured in the presence of c-myb senseor antisense oligodeoxynucleotides; cell viability and cloningefficiency were then assessed. c-myb sense oligomers had neg-ligible effects on normal and leukemic cells. In contrast, c-mybantisense oligomers strongly inhibited or completely abolishedclonogenic growth of a T-cell leukemia line, 78% (18 of 23) ofprimary acute myelogenous leukemia cases examined, and 4 of5 primary chronic myelogenous leukemia (CML) cases in blastcrisis. In three of the latter patients, polymerase chain reactionanalysis of a 1:1 mixture of c-myb antisense-treated normal andCML cells revealed a complete absence of ber-abl expression,suggesting that the CML clonogenic units had been completelyeliminated from the cultures. At antisense doses that inhibitedleukemic cell growth, normal hematopoietic progenitor cellssurvived. Thus, normal and leukemic hematopoietic cells showdifferential sensitivity to the toxic effects of c-myb antisenseDNA. Perturbation of c-myb function with antisense oligode-oxynucleotides might eventually form the basis for a molecularapproach to leukemia therapy, perhaps most immediately as exvivo bone marrow purging agents