Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene.
There is substantial evidence to suggest that aberrant DNA methylation in the regulatory regions of expressed genes may play a role in hematologic malignancy. In the current report, the Restriction Landmark Genomic Scanning (RLGS) method was used to detect aberrant DNA methylation (M) in acute myeloid leukemia (AML). RLGS-M profiles were initially performed using DNA from diagnostic, remission, and relapse samples from a patient with AML. Rp18, one of the eight spots found that was absent in the relapse sample, was cloned. Sequence analysis showed that the spot represented a portion of the WIT-1 gene on human chromosome 11p13. Rp18 was missing in the relapse sample due to a distinct DNA methylation pattern of the WIT-1 gene. Twenty-seven AML patients that entered CR after therapy (i.e., chemosensitive) were studied and only 10 (37%) of the diagnostic bone marrow (BM) samples showed methylation of WIT-1. However, seven of eight (87.5%) diagnostic BM samples from primary refractory AML (chemosensitive) showed methylation of WIT-1. The incidence of WIT-1 methylation in primary refractory AML was significantly higher than that noted in chemosensitive AML (P=0.018). Together, these results indicate that RLGS-M can be used to find novel epigenetic alterations in human cancer that are undetectable by standard methods. In addition, these results underline the potential importance of WIT-1 methylation in chemoresistant AML.
Plass
C
C
Department of Microbiology and Immunology, Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.
Yu
F
F
Yu
L
L
Strout
M P
MP
El-Rifai
W
W
Elonen
E
E
Knuutila
S
S
Marcucci
G
G
Young
D C
DC
Held
W A
WA
Bloomfield
C D
CD
Caligiuri
M A
MA
D000208:Acute Disease; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D012008:Recurrence
D004273:DNA, Neoplasm