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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2075-2080
Methylation of the ABL1 Promoter in Chronic Myelogenous
Leukemia: Lack of Prognostic Significance
Jean-Pierre J. Issa,
Hagop Kantarjian,
Avinash Mohan,
Susan O'Brien,
Jorge Cortes,
Sherry Pierce, and
Moshe Talpaz
From The Johns Hopkins Oncology Center, Baltimore, MD; and The MD
Anderson Cancer Center, Houston, TX.
The BCR-ABL chromosomal translocation is a central event in
the pathogenesis of chronic myelogenous leukemia (CML). One of the
ABL1 promoters (Pa) and the coding region of the gene are usually translocated intact to the BCR locus, but the
translocated promoter appears to be silent in most cases. Recently,
hypermethylation of Pa was demonstrated in CML and was proposed to mark
advanced stages of the disease. To study this issue, we measured Pa
methylation in CML using Southern blot analysis. Of 110 evaluable
samples, 23 (21%) had no methylation, 17 (15%) had minimal (<15%)
methylation, 12 (11%) had moderate methylation (15% to 25%), and 58 (53%) had high levels of methylation (>25%) at the ABL1
locus. High methylation was more frequent in advanced cases of CML.
Among the 76 evaluable patients in early chronic phase (ECP), a major
cytogenetic response with interferon-based therapy was observed in 14 of 34 patients with high methylation compared with 19 of 42 among the
others (41% v 45%; P value not significant). At a
median follow-up of 7 years, there was no significant difference in
survival by ABL1 methylation category. Among patients who
achieved a major cytogenetic response, low levels of methylation were
associated with a trend towards improved survival, but this trend did
not reach statistical significance. Thus, Pa methylation in CML is
associated with disease progression but does not appear to predict for
survival or response to interferon-based therapy.
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