Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.
OBJECTIVE
Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies.


METHODS
In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction.


RESULTS
The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). INTERPRETATIONS AND CONCLUSION: The methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome.
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
Castillejo
Juan A
JA
Navarro
German
G
San Jose-Eneriz
Edurne
E
Garate
Leire
L
Cordeu
Lucia
L
Cervantes
Francisco
F
Prosper
Felipe
F
Heiniger
Anabel
A
Torres
Antonio
A
D000951:Antigens, Neoplasm / Q000097:blood*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D018899:CpG Islands; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000502:physiology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007372:Interferons / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000378:metabolism
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D007372:Interferons; C412324:DDX43 protein, human; D053487:DEAD-box RNA Helicases