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Matilda Logan
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1 1393/5/21: 1393/8/12: 1393 "# $!/306 / DKK1WIF1 Wnt!"# $ %& ' ( ) ! "# "* ('+ ' () *+,- %&!!! "# (Acute myeloid leukemia AML) : ;.< DNA,9 : p73 CDKN2B (7 '& ",,+ 6+!. 4& 5AML '., 3! (!./ 0&1 '.,-Wnt 'A1 3 B,!",,+?@,& 5(Dickkopf1) DKK1 (Wnt inhibitory factor1) WIF1!=>&1.-.D9# 'G ' ' AML * < F.' ' DKK1 WIF1!..< D4E 5E *4C '& B? IJ!* DNA.- * 9#!-.,) *? 9 30 AML * < F ' 120. * :!1 (Methylation specific-polymerase chain reaction) MSP %,K& 5!..< D4E '.# '.- "B DKK1 WIF1!. * N * & LM!* A+ R! '. (34/120) L' 28/3 (42/120) 35/0 P&& * DKK1 WIF1!..< O! L' : DKK1. (P = 0/0030) WIF1..< O! = T.T "!T. =.< 5? 9 * S *+!-.- "!T AML-M0 "#.' ' (P = 0/0050) VB& 0 AML ' DKK1 WIF1!..< 51&!'& '3,! *+ - "!T E *4C ' :.- * - XY ' Z- '!. =.< *+ ' W ' =. 9 % < 5Dickkopf1 5Wnt inhibitory factor 1 5DNA.< : )* + Wnt '(" # $%&.VL.F) 5?\+ 'BN 5]F) :G 5=3[ [ 5) G :! K-01 "KT *^../ , '.(,4 / %5./ DKK1 WIF1,(% :(306) 32 `1393._BL, - & " ( )*% + 01 & "/! " AML 37%8.(1) - 5" /&/, ;78."4% & / : Acute myeloid leukemia) (AML! "#$% & ' a.qasemi2012@yahoo.com &!"# $ % -1 &!"# $ % %( -2 & + +!"# $ % (* -3 : !" #$ /306 / 32

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5 %&' $ DKK1 7 " (m 8/82) 3, WIF1 7 Q C qt% &? p. & "l M DKK1, WIF1 7 "l.(p = 0/552, P = 0/149 b%"% &) 5 ' & q".m\ Qr Q. / 5' (m 90/8) 109 ' k8 (m 79/1) 95 +C% 30 b%"% & +C% Q & ' ET! B & "l DKK1, WIF1 7 " 24,.(P = 0/211, P = 0/143 b%"% ' & (m 27/5) 33 9, 14 b%"% & +C% Q & + Y,@ p. & "l DKK1, WIF1 7 " 7 "l Q C qt% &?,, Q DKK1, WIF1."A 5 ' k8 E T!,,"< =2% AML & T b%"% & DKK1, WIF1 7, "l 34) m 28/3, ( 120 "U 42) m 35 m 29/1 Qr. ( 120 "U 7 " =2% ( 120 "U 35).(1,/) & DKK1, WIF1 " Y% 7 Q /& Q". ' 5 FAB-AML,"?, (P = 0/003) WIF1 7 "l FAB-0 5,"? " qt% (P = 0/005) DKK1 qt% &? p.(1,/) ' 5 AML-M, WIF1 7 "l Q C +k/ E' =' DKK1 5-8, U T? J ' +Q M B 120 "U 16 C%.(1,/) " (m 16/6) 7 +Q Q & 5' (Acute myeloid leukemia) AML $#?@3A $), +3* DKK1 WIF1 # <3# = >5.1 :; P (Dickkopf1) DKK1 86 (71/6) 34 (28/3) 0/781 42/5(17-68) 43(22-64) 0/ /201 13/2 64/1 0/ /185 8/9 8/3 0/005 3(3/4) 7 (20/5) 0/ (22) 7 (20/5) 0/ (30/2) 6 (17/6) 0/ (20/9) 4 (11/7) 0/ (18/6) 2(5/8) 0/ (11/6) 2(5/8) 0/ (82/5) 24 (70/5) 0/999 4(4/6) 1(2/9) 0/ (15/1) 3(8/8) FAB: French American British (Wnt inhibitory factor1) WIF1 P 0/285 0/217 0/278 0/694 0/280 0/003 0/817 0/525 0/466 0/288 0/538 0/143 0/137 0/ (65) 39(18-60) / /7 2(2/5) 16 (20/5) 22 (28/2) 16 (20/5) 14 (17/9) 9 (11/5) 65 (83/3) 2(2/5) 9 (11/5) 42 (35) 42/5(22-63) /5 115/4 8/3 8 (19/0) 10 (23/8) 10 (23/8) 6 (14/2) 4(9/5) 3(7/1) 30 (71/4) 3(7/1) 7 (16/6) (),-./ (5 612) 3 4$ : () 859 ; (10 9 /l), 6 $<= > 3,?, (10 9 > 3,?, (g/dl) 3,-$=$ C,D 3,?, M0./ EFAB 65-1:= M1 () M2 M4 M5 M6 GA 6$<-./ H: () $I !" #$ /306 / 32

6 %&'$ "> "A 5!."A SFRP 7 Wnt Y8 xc +(Secreted frizzled-related protein).(23) - 5' 5 AML & / & &C0 $, Yu M & DKK1 7 %,"8 +Wnt/β-catenin Y8 "> ->?P \" & T!?PR8 qt% &>@ $78.K.(24) ' 5C I%, > "L8 -?" $7."4% -P-5, AZA & / DNA 5 & EM & Q >-2, Cooper.(3-6) ' + R@ SFRP & "!8 %@@1% C $ / y%" ; - Q$ +b"% "A $) SFRP & ' \" "! P (Wnt Y8 "> 5! 11 Y,,", " DKK1 7.(25) - 5', > \" 5 3% & + "* & / > \" i +(26-27) & z 3 ;U, (26) > & - Q$ Qr. D" (28).' {"0 % 5 D" 7 ; M 7 " /& m 72/5) 87 &C0 Q DKK1, WIF1 " (m 61/6) 74, WIF1 " (m 7 Q Q"."? 5 DKK1 Y8 "> W[% "\ - Q$ }"\.' &' - AML i,"' +Wnt > Wnt/β-catenin Y8 "> QC% +"#$% +-" +7< & / "<. - E? E$%, -'" +@ Wnt/β-catenin Y8 "> R@ t & XM + 3%, "#$% Q & - 5' &g"< Q P /, 37%8 $ + Y8 "> DKK1, WIF1.(18-20) ' &' R@ & > % 5 D" QV%,"8 Wnt/β-catenin Y8 "> 5 EC% Wnt QV%,"8 & d% QV%,"8 Q.'.' Wnt 5"? & P d% e Wnt Y8 "> ' C< "a bt +&: Q \T% - Q$ +, Q."? Wnt Y8 "> ->?P 7, "8% % "> Q ' C<,.(19-20) ' &' /, $ + % 5 D" 7 /& "# $7 v Q"%u, Q"%md.(21-22) ' > \" 7 -Cg, +"g &C0 AML & T DKK1, WIF1 Em u.-<"? "* " =2% 7 "l & &C0 Q m 35,"< b%"% & DKK1, WIF1 120 "U 34) m 28/3, ( 120 "U 42) =2% AML & T ( ; p &.< wu% 5 7 Q +U ' & 1393!" #$ /306 /

7 %&' $ m 80 WIF1 7 "l Q" = 0/0050) m 70 DKK1 7, (P = 0/0030) AML-M5 5,"? " &.' (P m 22/2 WIF1 7 "l Q" m 11/11 DKK1 7, (P = 0/2280).< wu% (P = 0/0940),"< & "!8 $, Hou "l 5" & DKK1 7 "l.(p < 0/0001) < wu% SFRP 5.(31) (P = 0/7640) -> 5" WIF1 & Q C qt% &? p +&C0 Q EM, DKK1, WIF1 7 "l J ', Q Y" 5!?PR8. 5 AML U T? Q Q C qt% p Qr +k/ &d' "A, 7 Q."A 5 Q?, -8 J ' & 5 R3< IT%" - Q$ ' k Q.' 5 E T! (m 79/1) 95 m 5 " x & E T!. 5' J ' `1d%, " E <,"% J ') " -8 J ' +","$ 1000 " Q? +","$ (01 - x YM, 10 g/dl R & K Qr.' w\ " ' 2 34 m 20.(32) ' &' /, + 5 & C qt% &? p +"g &C0 Q qt% ; $, Suzuki +"A DKK1 %,"8 R.(29) "!8 "l,"< +"g &C0, m 35 b%"% &) DKK1, WIF1 7 & "? 5 (m 63/3 E +m 28/3 b%"% &) $, Griffiths J 3? ", (30) (m 48 E +m 16, m 32, m 26 b%"% &) $, Hou J 3? Q.(31) (m 56/1E +m 30/1 D2.,U% ' - Q$.< 3 "g &C0.' y i%, DKK1, WIF1 7 & "A.C0 > AML $7 5 EC% }."? C< "a T & & & &C0 \ $, Hou "> 5! "l Q" M0 5,"? " AML Wnt Y8 Q" & + ~ (m 100) " (P = 0/0006 m 48/3) "l, Hou Qr.(31) < wu% M4/M5 5,"? DKK1 7 & " J 3? $ 0/0105 m 75) "%e' AML-M0 5,"? " M1 5,"? " " WIF1 7, (P = m 42/1 b%"% &) M3, wu% (P = 0/0005 m 63/2, P = 0/0035 & "g &C0.(31) < 5,"? " Y% 7 Q /& M6, M5 +M4 +M2 +M1 +M0 E' FAB-AML AML-M0 5,"? ".< wu% !" #$ /306 / 32

8 %&'$ & T & C% ".C0 \ &.- "[ Q -T#% " " AML "3/ & &C0 Q +&m e' 58 ; DKK1, WIF1 7 CpG ->?P &C0, - AML.' &m% Wnt Y8 "> "A! 5A,<,.@@1% -,C &, Q &C0 Q "/ &3 & "!% $'38 Y M."? * + Qo%, DKK1, WIF1 7 "l Q ' k8 E T!,, & 8, "A, Chim &B "?. >$ "l ; WIF1 & (33) $ " )Cg 5!?PR8 &>, "a EM Valencia +' (Disease-free survival) DFS & T & (34) $, +Wnt 5! & 7 B Q' AML RFS "%)Cg!?PR8.> (Relapse-free survival) References 1. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999; 341(14): Galm O, Herman JG. Methylation-specific polymerase chain reaction. Methods Mol Med 2005; 113: Gilbert J, Gore SD, Herman JG, Carducci MA. The clinical application of targeting cancer through histone acetylation and hypomethylation. Clin Cancer Res 2004; 10(14): Claus R, Almstedt M, Lubbert M. Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. Semin Oncol 2005; 32(5): Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109(1): Plimack ER, Kantarjian HM, Issa JP. Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma 2007; 48(8): Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF- 1 (DKK-1) gene in human colorectal cancer. Oncogene 2006; 25(29): Parkin D, Whelan S, Ferlay J, Teppo L, Thomas D. Cancer incidence in five continents. Volume VIII. IARC Sci Publ 2002; (155): Jost E, Schmid J, Wilop S, Schubert C, Suzuki H, Herman JG, et al. Epigenetic inactivation of secreted Frizzled-related proteins in acute myeloid leukaemia. Br J Haematol 2008; 142(5): Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008; 8(5): Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocytemacrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351(7): Paul S, Dey A. Wnt signaling and cancer development: therapeutic implication. Neoplasma 2008; 55(3): Jones SE, Jomary C. Secreted Frizzled-related proteins: searching for relationships and patterns. Bioessays 2002; 24(9): Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, et al. Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 2005; 65(16): Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J. Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci 2008; 1393!" #$ /306 /

9 %&' $ 121(Pt 6): Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3): Huang J, Zhang YL, Teng XM, Lin Y, Zheng DL, Yang PY, et al. Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma. BMC Cancer 2007; 7: Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001; 1(1): Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 2007; 21(8): Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429(6990): Nakamoto D, Yamamoto N, Takagi R, Katakura A, Mizoe JE, Shibahara T. Detection of microsatellite alterations in plasma DNA of malignant mucosal melanoma using whole genome amplification. Bull Tokyo Dent Coll 2008; 49(2): Ghasemi A, Nadali F, Chahardouli B, Alizad Ghandforosh N, Ghavamzadeh A, Rostami Sh. Study of correlation between SFRP-1 and SFRP-2 hypermethylation with relapse, complete remission, genetic mutations of FLT3- ITD and NPM1 and immunophenotypes of leukemic cells in patients with de novo acute myeloblastic leukemia. J Hematol 2014; 3(2): Yu J, Tao Q, Cheng YY, Lee KY, Ng SS, Cheung KF, et al. Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer. Cancer 2009; 115(1): Cooper SJ, von Roemeling CA, Kang KH, Marlow LA, Grebe SK, Menefee ME, et al. Reexpression of tumor suppressor, sfrp1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers. Mol Cancer Ther 2012; 11(10): Kurose K, Sakaguchi M, Nasu Y, Ebara S, Kaku H, Kariyama R, et al. Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma. J Urol 2004; 171(3): Nozaki I, Tsuji T, Iijima O, Ohmura Y, Andou A, Miyazaki M, et al. Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer. Int J Oncol 2001; 19(1): Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Barrios M, et al. Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia. Br J Cancer 2004; 91(4): Suzuki R, Onizuka M, Kojima M, Shimada M, Fukagawa S, Tsuboi K, et al. Preferential hypermethylation of the Dickkopf-1 promoter in core-binding factor leukaemia. Br J Haematol 2007; 138(5): Griffiths EA, Gore SD, Hooker C, McDevitt MA, Karp JE, Smith BD, et al. Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk Lymphoma 2010; 51(9): Hou HA, Kuo YY, Liu CY, Lee MC, Tang JL, Chen CY, et al. Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia. Br J Cancer 2011; 105(12): Smith M, Barnett M, Bassan R, Gatta G, Tondini C, Kern W. Adult acute myeloid leukaemia. Crit Rev Oncol Hematol 2004; 50(3): Chim CS, Chan WW, Pang A, Kwong YL. Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia: an independent poor prognostic factor. Leukemia 2006; 20(5): Valencia A, Roman-Gomez J, Cervera J, Such E, Barragan E, Bolufer P, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia 2009; 23(9): !" #$ /306 / 32

10 Journal of Isfahan Medical School Received: Vol. 32, No. 306, 3 rd Week, December 2014 Accepted: Dysregulation of the Wnt Signaling Pathway through Methylation of WIF1and DKK1 Genes in Patients with Acute Myeloid Leukemia (AML) at the Time of Diagnosis Abstract Ali Ghasemi MSc 1, Mohsen Mohammadi PhD 2, Abbas Ghotaslou MSc 1, Kazem Ghaffari MSc 3, Sadegh Abbasian MSc 1 Original Article Background: In acute myeloid leukemia (AML), a large number of tumor suppressor genes are silenced through DNA methylation such as CDKN2B and p73. Wnt inhibitory factor 1 (WIF1) and Dickkopf-1 (DKK-1) are negative regulator of the Wnt signaling pathway. In the present study, we studied the methylation status of WIF1 and DKK-1 genes in patients with acute myeloid leukemia. Methods: Blood samples from 120 patients with acute myeloid leukemia and 25 healthy control subjects were taken. Isolated DNA was treated with sodium bisulphite and examined via methylationspecific polymerase chain reaction (MSP) with primers specific for methylated and unmethylated sequences of the WIF1 and DKK-1 genes. Findings: The frequency of aberrant hypermethylation of WIF1 and DKK-1 genes in patients with acute myeloid leukemia was determined 35.0% (42/120) and 28.3% (34/120), respectively. In addition, for all subjects in control group, methylation of WIF1 and DKK-1 genes were negative. Patients with M0 subtype of French-American-British acute myeloid leukemia (FAB-AML) had the highest incidence of hypermethylation of WIF1 (P = 0.003) and DKK-1 (P = 0.005) genes. Conclusion: The present study showed that, like many solid tumors, WIF1 and DKK-1 genes methylation also occurs in acute myeloid leukemia. Therefore, the methylation of these genes may play a role in leukmogenesis initiation. Keywords: DNA Methylation, WIF1, DKK, Acute myeloid leukemia Citation: Ghasemi A, Mohammadi M, Ghotaslou A, Ghaffari K, Abbasian S. Dysregulation of the Wnt Signaling Pathway through Methylation of WIF1and DKK1 Genes in Patients with Acute Myeloid Leukemia (AML) at the Time of Diagnosis. J Isfahan Med Sch 2014; 32(306): Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran 2- Department of Biotechnology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran 3- Instructor, Department of Hematology, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran Corresponding Author: Ali Ghasemi MSc, a.qasemi2012@yahoo.com 1393!" #$ /306 /

Concomitant WT1 mutations predicted poor prognosis in CEBPA double-mutated acute myeloid leukemia

Concomitant WT1 mutations predicted poor prognosis in CEBPA double-mutated acute myeloid leukemia Feng-Ming Tien, Hsin-An Hou, Jih-Luh Tang, Yuan-Yeh Kuo, Chien-Yuan Chen, Cheng-Hong Tsai, Ming Yao, Chi-Cheng