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Acute- and chronic-phase chronic myelogenous leukemia colony-forming units
are highly sensitive to the growth inhibitory effects of c-myb antisense
oligodeoxynucleotides
MZ Ratajczak, N Hijiya, L Catani, K DeRiel, SM Luger, P McGlave and AM Gewirtz
Department of Pathology, University of Pennsylvania School of Medicine,
Philadelphia 19104.
We have previously demonstrated that malignant hematopoietic colony-
forming units (CFUs) may be purged from normal CFU by exposure to c-myb
antisense oligodeoxynucleotides (oligomers). This novel strategy appeared
particularly promising for patients with chronic myelogenous leukemia (CML)
in blast crisis, since in some cases complete elimination of
bcr-abl-expressing cells was accomplished. We have examined 11 additional
patients, including seven in chronic phase, in order to extend these
initial observations. We sought in particular to determine if elimination
of bcr-abl-expressing clones was a usual event. Exposure of CML cells to
c-myb antisense oligomers resulted in inhibition of CFU-granulocyte,
macrophage (CFU-GM)-derived colony formation in eight of 11 (73%) cases
evaluated. Inhibition was antisense sequence-specific, dose-dependent,
ranged between 58% and 93%, and was statistically significant (P less than
or equal to .03) in seven of the eight cases. In two cases,
CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM)-derived
colony formation was also examined and found to be inhibited by the c-myb
antisense oligomers in a sequence-specific manner. To determine whether CML
CFU had been reduced or eliminated after exposure to the antisense
oligomers, we examined cells in the residual colonies for bcr-abl mRNA
expression using a reverse transcription-polymerase chain reaction
detection technique (RT-PCR). Eight cases were evaluated and in each case
where antisense myb inhibited growth, bcr-abl expression as detected by RT-
PCR was either greatly decreased or nondetectable. No residual leukemic CFU
were demonstrable on replating of treated cells. These results suggest that
c-myb antisense oligomers substantially inhibit the growth and survival of
CML CFU in both chronic and blast phase of disease. They may therefore
prove useful for both ex vivo and in vivo treatment of CML.
Volume 79,
Issue 8,
pp. 1956-1961,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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