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DNA Methylation Studies

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

Leukemia volume 15, pages 575–582 (2001)Cite this article

Abstract

In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABLis rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Ph-positive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation.

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References

  1. LeBeau MM, Rowley JD . Heritable fragile sites in cancer Nature 1984 308: 607–608

    Article  CAS  PubMed  Google Scholar 

  2. Saglio G, Pane F, Martinelli G, Guerrasio A . BCR/ABL rearrangement and leukemia phenotype Leukemia 1999 13: (Suppl. 1) S96

    Article  PubMed  Google Scholar 

  3. Hochhaus A, Reiter A, Skladny H, Melo JV, Sick C, Berger U, Guo JQ, Arlinghaus RB, Hehlmann R, Goldman JM, Cross NC . A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia Blood 1996 88: 2236–2240

    CAS  PubMed  Google Scholar 

  4. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G . Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22 Cell 1984 36: 93–99

    Article  CAS  PubMed  Google Scholar 

  5. Fainstein E, Marcelle C, Rosner A, Canaani E, Gale RP, Dreazen O, Smith SD, Croce CM . A new fused transcript in Philadelphia chromosome positive acute lymphocytic leukaemia Nature 1987 330: 386–388

    Article  CAS  PubMed  Google Scholar 

  6. Konopka JB, Watanabe SM, Singer JW, Collins SJ, Witte ON . Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration Proc Natl Acad Sci USA 1985 82: 1810–1814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene Science 1986 233: 212–214

    Article  CAS  PubMed  Google Scholar 

  8. Kurzrock R, Shtalrid M, Romero P, Kloetzer WS, Talpas M, Trujillo JM, Blick M, Beran M, Gutterman JU . A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia Nature 1987 325: 631–635

    Article  CAS  PubMed  Google Scholar 

  9. Clark SS, McLaughlin J, Crist WM, Champlin R, Witte ON . Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL Science 1987 235: 85–88

    Article  CAS  PubMed  Google Scholar 

  10. Chan LC, Karhi KK, Rayter SI, Heisterkamp N, Eridani S, Powles R, Lawler SD, Groffen J, Foulkes JG, Greaves MF, Wiedemann LM . A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia Nature 1987 325: 635–637

    Article  CAS  PubMed  Google Scholar 

  11. Zion M, Ben-Yehuda D, Avraham A, Cohen O, Wetzler M, Melloul D, Ben-Neriah Y . Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia Proc Natl Acad Sci USA 1994 91: 10722–10726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ben-Yehuda D, Krichevsky S, Rachmilewitz EA, Avraham A, Palumbo GA, Frassoni F, Sahar D, Rosenbaum H, Paltiel O, Zion M, Ben-Neriah Y . Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia Blood 1997 90: 4918–4923

    CAS  PubMed  Google Scholar 

  13. Asimakopoulos FA, Shteper PJ, Krichevsky S, Fibach E, Polliack A, Rachmilewitz E, Ben-Neriah Y, Ben-Yehuda D . ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia Blood 1999 94: 2452–2460

    CAS  PubMed  Google Scholar 

  14. Kantarjian HM, Talpaz M, Dhingra K, Estey E, Keating MJ, Ku S, Trujillo J, Huh Y, Stass S, Kurzrock R . Significance of the P210 vs P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia Blood 1991 78: 2411–2418

    CAS  PubMed  Google Scholar 

  15. Issa JP, Kantarjian H, Mohan A, O'Brien S, Cortes J, Pierce S, Talpaz M . Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance Blood 1999 93: 2075–2080

    CAS  PubMed  Google Scholar 

  16. Willer A, Kramer A, Saussele S, Hochhaus A, Seifath W, Hehlmann R . Disease progression in chronic myelogenous leukemia (CML) is linked to methylation of the ABL promoter Blood 1997 90: 196a (Abstr.)

    Google Scholar 

  17. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science 1990 247: 1079–1082

    Article  CAS  PubMed  Google Scholar 

  18. Ilaria RLJ, Van Etten RA . The SH2 domain of P210BCR/ABL is not required for the transformation of hematopoietic factor-dependent cells Blood 1995 86: 3897–3904

    PubMed  Google Scholar 

  19. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N . BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice Blood 1995 86: 4603–4611

    CAS  PubMed  Google Scholar 

  20. Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K, Ishikawa T, Yazaki Y, Hirai H . Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias Blood 1998 91: 2067–2075

    CAS  PubMed  Google Scholar 

  21. Li S, Ilaria RLJ, Million RP, Daley GQ, Van Etten RA . The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity J Exp Med 1999 189: 1399–1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schenk TM, Keyhani A, Bottcher S, Kliche KO, Goodacre A, Guo JQ, Arlinghaus RB, Kantarjian HM, Andreeff M . Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia Leukemia 1998 12: 666–674

    Article  CAS  PubMed  Google Scholar 

  23. Graff JR, Herman JG, Myöhänen S, Baylin SB, Vertino PM . Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation J Biol Chem 1997 272: 22322–22329

    Article  CAS  PubMed  Google Scholar 

  24. Chissoe SL, Bodenteich A, Wang YF, Wang YP, Burian D, Clifton SW, Crabtree J, Freeman A, Iyer K, Jian L, Ma Y, McLaury H-J, Pan H-Q, Sarhan OH, Toth S, Wang Z, Zhang G, Heistercamp N, Groffen J, Roe BA . Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation Genomics 1995 27: 67–82

    Article  CAS  PubMed  Google Scholar 

  25. Jiang XY, Trujillo JM, Liang JC . Chromosomal breakpoints within the first intron of the ABL gene are nonrandom in patients with chronic myelogenous leukemia Blood 1990 76: 597–601

    CAS  PubMed  Google Scholar 

  26. Chen SJ, Chen Z, Hillion J, Grausz D, Loiseau P, Flandrin G, Berger R . Ph1-positive, bcr-negative acute leukemias: clustering of breakpoints on chromosome 22 in the 3′ end of the BCR gene first intron Blood 1989 73: 1312–1315

    CAS  PubMed  Google Scholar 

  27. Cameron EE, Baylin SB, Herman JG . p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing Blood 1999 94: 2445–2451

    CAS  PubMed  Google Scholar 

  28. Ohtani-Fujita N, Fujita T, Aoike A, Osifchin NE, Robbins PD, Sakai T . CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene Oncogene 1993 8: 1063–1067

    CAS  PubMed  Google Scholar 

  29. Nguyen TT, Mohrbacher AF, Tsai YC, Groffen J, Heisterkamp N, Nichols PW, Yu MC, Lubbert M, Jones PA . Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications Blood 2000 95: 2990–2992

    CAS  PubMed  Google Scholar 

  30. de Wind N, Dekker M, Berns A, Radman M, te Riele H . Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer Cell 1995 82: 321–330

    Article  CAS  PubMed  Google Scholar 

  31. Reitmair AH, Schmits R, Ewel A, Bapat B, Redston M, Mitri A, Waterhouse P, Mittrücker HW, Wakeham A, Liu B, Thomason A, Griesser H, Gallinger S, Ballhausen WG, Fishel R, Mak TW . MSH2 deficient mice are viable and susceptible to lymphoid tumours Nat Genet 1995 11: 64–70

    Article  CAS  PubMed  Google Scholar 

  32. Edelmann W, Yang K, Umar A, Heyer J, Lau K, Fan K, Liedtke W, Cohen PE, Kane MF, Lipford JR, Yu N, Crouse GF, Pollard JW, Kunkel T, Lipkin M, Kolodner R, Kucherlapati R . Mutation in the mismatch repair gene Msh6 causes cancer susceptibility Cell 1997 91: 467–477

    Article  CAS  PubMed  Google Scholar 

  33. Indraccolo S, Minuzzo S, Nicoletti L, Cretella E, Simon M, Papakonstantinou G, Hehlmann R, Mion M, Bertorelle R, Roganovic J, Chieco-Bianchi L . Mutator phenotype in human hematopoietic neoplasms and its association with deletions disabling DNA repair genes and bcl-2 rearrangements Blood 1999 94: 2424–2432

    CAS  PubMed  Google Scholar 

  34. Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN . Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability Cancer Res 1998 58: 3455–3460

    CAS  PubMed  Google Scholar 

  35. Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD . Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers Proc Natl Acad Sci USA 1998 95: 8698–8702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB . Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma Proc Natl Acad Sci USA 1998 95: 6870–6875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R . Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines Cancer Res 1997 57: 808–811

    CAS  PubMed  Google Scholar 

  38. Batova A, Diccianni MB, Yu JC, Nobori T, Link MP, Pullen J, Yu AL . Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia Cancer Res 1997 57: 832–836

    CAS  PubMed  Google Scholar 

  39. Leegwater PA, Lambooy LH, De Abreu RA, Bökkerink JP, van den Heuvel LP . DNA methylation patterns in the calcitonin gene region at first diagnosis and at relapse of acute lymphoblastic leukemia (ALL) Leukemia 1997 11: 971–978

    Article  CAS  PubMed  Google Scholar 

  40. Nakamura M, Sugita K, Inukai T, Goi K, Iijima K, Tezuka T, Kojika S, Shiraishi K, Miyamoto N, Karakida N, Kagami K, O-Koyama T, Mori T, Nakazawa S . p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation Leukemia 1999 13: 884–890

    Article  CAS  PubMed  Google Scholar 

  41. Kawamura M, Ohnishi H, Guo SX, Sheng XM, Minegishi M, Hanada R, Horibe K, Hongo T, Kaneko Y, Bessho F, Yanagisawa M, Sekiya T, Hayashi Y . Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia Leukemia Res 1999 23: 115–126

    Article  CAS  Google Scholar 

  42. Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG . Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5′ CpG island methylation Cancer Res 1999 59: 3352–3356

    CAS  PubMed  Google Scholar 

  43. Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Döhner H . Biallelic mutations in the ATM gene in T-prolymphocytic leukemia Nature Med 1997 3: 1155–1159

    Article  CAS  PubMed  Google Scholar 

  44. Luo L, Lu FM, Hart S, Foroni L, Rabbani H, Hammarström L, Yuille MR, Catovsky D, Webster AD, Vorechovsky I . Ataxia-telangiectasia and T-cell leukemias: no evidence for somatic ATM mutation in sporadic T-ALL or for hypermethylation of the ATM-NPAT/E14 bidirectional promoter in T-PLL (published erratum appears in Cancer Res 1998; 58: 3488) Cancer Res 1998 58: 2293–2297

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grants from the Gabriella Rich Leukemia Fund, the Foulkes Foundation, the Office of the Chief Scientist of the State of Israel, the Israel Science Foundation, the Yael Foundation, and the Golda Meir Fellowship Fund. We thank Ilana Sverdlin for her skilled technical assistance.

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Authors and Affiliations

  1. Department of Hematology, Hadassah University Hospital, Jerusalem, Israel

    PJ Shteper, Z Siegfried, FA Asimakopoulos, EA Rachmilewitz & D Ben-Yehuda

  2. Department of Hematology, University of Catania, Catania, Italy

    GA Palumbo

  3. Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Y Ben-Neriah

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Shteper, P., Siegfried, Z., Asimakopoulos, F. et al. ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL. Leukemia 15, 575–582 (2001). https://doi.org/10.1038/sj.leu.2402026

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