Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation.
Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
Griffiths
Elizabeth A
EA
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Gore
Steven D
SD
Hooker
Craig
C
McDevitt
Michael A
MA
Karp
Judith E
JE
Smith
B Douglas
BD
Mohammad
Helai P
HP
Ye
Ying
Y
Herman
James G
JG
Carraway
Hetty E
HE
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015398:Signal Transduction; D015996:Survival Rate; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051153:Wnt Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C118511:SFRP5 protein, human
Crit Rev Oncol Hematol. 2005 Nov;56(2):195-221
16236521
J Gastrointest Surg. 2008 Oct;12(10):1745-53
18716850
Oncogene. 2005 Mar 31;24(14):2410-20
15735743
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
8790415
Br J Haematol. 2004 Aug;126(3):313-9
15257703
Hum Mol Genet. 2001 Dec 15;10(26):3001-7
11751682
Eur J Haematol. 2009 Mar;82(3):165-75
19067737
Hematology Am Soc Hematol Educ Program. 2009;:523-31
20008237
Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4467-73
17671131
N Engl J Med. 2008 May 1;358(18):1909-18
18450602
Epigenetics. 2008 Mar-Apr;3(2):59-63
18398311
Carcinogenesis. 2008 May;29(5):895-904
18308762
Leukemia. 2009 Sep;23(9):1658-66
19387464
Science. 2002 May 31;296(5573):1644-6
12040179
Leuk Res. 2003 Apr;27(4):313-21
12531222
Exp Hematol. 2005 Jul;33(7):719-37
15963848
Blood. 2002 Aug 1;100(3):982-90
12130512
Blood. 2005 May 1;105(9):3699-706
15650056
Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24
12781368
Blood. 2009 Oct 15;114(16):3448-58
19652201
Br J Haematol. 2008 Sep;142(5):745-53
18537968
Breast Cancer Res Treat. 2009 Mar;114(2):315-25
18404369
Biol Blood Marrow Transplant. 2000;6(1):50-7
10707999
Nat Genet. 2002 Dec;32(4):594-605
12426568
Nat Med. 2004 Jan;10(1):55-63
14702635
Leukemia. 2006 Jul;20(7):1211-6
16688229
Cancer Res. 2002 Aug 1;62(15):4519-24
12154064
Nat Genet. 2004 Apr;36(4):417-22
15034581
Cancer Sci. 2010 Feb;101(2):425-32
19874313
Leukemia. 2008 May;22(5):915-31
18288131
Blood. 1989 Oct;74(5):1499-506
2676014
PLoS Biol. 2004 Apr;2(4):E95
15024404
Histol Histopathol. 2006 Jul;21(7):761-74
16598675
Semin Oncol. 2008 Aug;35(4):336-45
18692684
Clin Cancer Res. 2007 Jul 15;13(14):4042-5
17634527
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3396-401
19218430
Br J Haematol. 2008 Feb;140(4):394-401
18217891
EMBO Rep. 2004 Dec;5(12):1181-6
15550930
J Cell Sci. 2008 Mar 15;121(Pt 6):737-46
18322270