Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia.
Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencing of retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronic-phase (CP, n=140) and the blast crisis (BC, n=47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (P<0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (P<0.0001) and c-MET gene antisense transcription (P<0.0001), and was significantly associated with high levels of BCR-ABL (P=0.02) and DNMT3b4 (P=0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P=0.004) or imatinib (P=0.034) and progression-free survival (P=0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.
Roman-Gomez
Jose
J
Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n. 14004, Cordoba, Spain. peperosa@teleline.es
Jimenez-Velasco
Antonio
A
Agirre
Xabier
X
Cervantes
Francisco
F
Sanchez
Joaquin
J
Garate
Leire
L
Barrios
Manuel
M
Castillejo
Juan A
JA
Navarro
German
G
Colomer
Dolors
D
Prosper
Felipe
F
Heiniger
Anabel
A
Torres
Antonio
A
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007372:Interferons / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000473:pathology / Q000628:therapy; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016366:Open Reading Frames; D010879:Piperazines / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D012044:Regression Analysis; D018626:Retroelements / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D000097584:DNA Methyltransferase 3B
D000970:Antineoplastic Agents; D001549:Benzamides; D004248:DNA (Cytosine-5-)-Methyltransferases; D000068877:Imatinib Mesylate; D007372:Interferons; D010879:Piperazines; D016315:Proto-Oncogene Proteins c-abl; D019859:Proto-Oncogene Proteins c-met; D011743:Pyrimidines; D018626:Retroelements; D000097584:DNA Methyltransferase 3B