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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-05-1598.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3205-3211
NEOPLASIA
JunB gene expression is inactivated by methylation in
chronic myeloid leukemia
Ming-Yu Yang,
Ta-Chih Liu,
Jan-Gowth Chang,
Pai-Mei Lin, and
Sheng-Fung Lin
From the Division of Hematology-Oncology, Department of
Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung,
Taiwan; Department of Molecular Medicine, China Medical
College Hospital, Taichung, Taiwan; and Department of
Nursing, I-Shou University, Kaohsiung, Taiwan.
JunB is a component of the Jun family genes of the activating
protein-1 transcription factors that are important in the control of
cell growth and differentiation and neoplastic transformation. Recently, it was demonstrated that transgenic mice specifically lacking
JunB expression in the myeloid lineage developed a myeloproliferative disease, eventually progressing to blast crisis that resembled human chronic myeloid leukemia (CML). To gain further insights into the
role of JunB in human CML, we examined peripheral blood from 17 healthy
individuals and CML patients (11 in blastic crisis and 21 in chronic
phase) by real-time quantitative reverse transcription-polymerase chain reaction analysis for the expression of JunB. The results showed
the expression levels of JunB were significantly impaired in CML cases
(blastic crisis < chronic phase < normal).
Mutational analysis of the whole gene and methylation analysis
of cytosine-phosphate guanosine (CpG) sites at the promoter
area were further performed to investigate the possible mechanisms.
However, no mutation was found within the coding region or the 9 flanking evolutionarily conserved regions in all CML cases.
Interestingly, in the promoter area of JunB gene, most of
the CpG sites were methylated in CML cases; in contrast, none of these
CpG sites were methylated in normal cases. Demethylation by treatment
of hypermethylated K562 cells with 5'-aza-2'-deoxycytidine
resulted in partial reactivation of JunB expression. Our results
suggest that the down-regulated JunB expression in CML was due to the
inactivation of JunB gene by methylation and the differential
expression was correlated to the ratio of cells being methylated.
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