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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2452-2460
ABL1 Methylation Is a Distinct Molecular Event Associated With
Clonal Evolution of Chronic Myeloid Leukemia
Fotis A. Asimakopoulos,
Pesach J. Shteper,
Svetlana Krichevsky,
Eitan Fibach,
Aaron Polliack,
Eliezer Rachmilewitz,
Yinon Ben-Neriah, and
Dina Ben-Yehuda
From the Department of Hematology, Hadassah University Hospital, and
Lautenberg Center for Immunology, Hebrew University-Hadassah Medical
School, Jerusalem, Israel.
Methylation of the proximal promoter of the ABL1 oncogene is
a common epigenetic alteration associated with clinical progression of
chronic myeloid leukemia (CML). In this study we queried whether both
the Ph'-associated and normal ABL1 alleles undergo
methylation; what may be the proportion of hematopoietic progenitors
bearing methylated ABL1 promoters in chronic versus acute phase
disease; whether methylation affects the promoter uniformly or in
patches with discrete clinical relevance; and, finally, whether
methylation of ABL1 reflects a generalized process or is
gene-specific. To address these issues, we adapted the techniques of
methylation-specific PCR and bisulfite-sequencing to study the
regulatory regions of ABL1 and other genes with a role in DNA
repair or genotoxic stress response. In cell lines established from CML
blast crisis, which only carry a single ABL1 allele nested
within the BCR-ABL fusion gene, ABL1 promoters
were universally methylated. By contrast, in clinical samples from
patients at advanced stages of disease, both methylated and
unmethylated promoter alleles were detectable. To distinguish between
allele-specific methylation and a mixed cell population pattern, we
studied the methylation status of ABL1 in colonies derived from
single hematopoietic progenitors. Our results showed that both
methylated and unmethylated promoter alleles coexisted in the same
colony. Furthermore, ABL1 methylation was noted in the vast
majority of colonies from blast crisis, but not chronic-phase CML. Both
cell lines and clinical samples from acute-phase CML showed nearly
uniform hypermethylation along the promoter region. Finally, we showed
that ABL1 methylation does not reflect a generalized process
and may be unique among DNA repair/genotoxic stress response genes. Our
data suggest that specific methylation of the Ph'-associated
ABL1 allele accompanies clonal evolution in CML.
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