Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome.
OBJECTIVE
Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy.


METHODS
Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment.


RESULTS
Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile.


CONCLUSIONS
We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Denmark.
Michael
M
Grövdal
Rasheed
R
Khan
Anni
A
Aggerholm
Petar
P
Antunovic
Jan
J
Astermark
Per
P
Bernell
Lena-Maria
LM
Engström
Lars
L
Kjeldsen
Olle
O
Linder
Lars
L
Nilsson
Anna
A
Olsson
Jonas
J
Wallvik
Jon Magnus
JM
Tangen
Gunnar
G
Oberg
Sten Eirik
SE
Jacobsen
Peter
P
Hokland
Anna
A
Porwit
Eva
E
Hellström-Lindberg
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000276:immunology; D015820:Cadherins / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D003562:Cytidine / Q000008:administration & dosage; D019175:DNA Methylation; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D011446:Prospective Studies; D012074:Remission Induction; D016896:Treatment Outcome
D018952:Antigens, CD34; D015820:Cadherins; D050762:Cyclin-Dependent Kinase Inhibitor p15; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D003562:Cytidine; D003630:Daunorubicin