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Proof of differentiative mode of action of all-trans retinoic acid in acute
promyelocytic leukemia using X-linked clonal analysis
S Elliott, K Taylor, S White, R Rodwell, P Marlton, D Meagher, J Wiley, D Taylor, S Wright and P Timms
Hematology Department, Mater Misericordiae Hospital, South Brisbane,
Queensland, Australia.
Using X-linked clonal analysis, mechanism of action of all-trans retinoic
acid (ATRA) was sought in a 16-year-old female with relapsed clonally
evolved acute promyelocytic leukemia (APL), who achieved complete
remission. On ATRA, metamorphosis of peripheral blood leukemic
promyelocytes to mature neutrophils was observed, despite the persistence
of t(15;17) in 100% of bone marrow metaphases. DNA was extracted from
fractionated serial blood specimens, collected at diagnosis, in first
complete remission (CR), relapse, and during ATRA treatment. Using a
phosphoglycerokinase (PGK) probe, the patient was heterozygous for both Bgl
I and Bst XI PGK polymorphisms. Methylation analysis showed monoclonal
leukemic promyelocytes with a polyclonal first CR achieved by standard
chemotherapy. Subsequent examination, in relapse, of granulocytes appearing
during ATRA treatment showed these to be monoclonal, proving these were
derived from the neoplastic clone. The X-linked clonal analysis methodology
has provided in vivo evidence of cellular differentiation as the mechanism
of action of ATRA. Parallel studies of cytogenetic and clonal analysis
showed a regression of the t(15;17) cytogenetic abnormality and return of a
polyclonal PGK methylation pattern in 5 weeks, indicating a repopulation of
marrow by normal stem cells. As standard cytogenetic techniques are
inappropriate for nondividing cells, X-linked clonal analysis provides a
marker system to allow insight into mechanism of drug action in malignant
hematologic disease.
Volume 79,
Issue 8,
pp. 1916-1919,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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