Abstract
Dysregulation of apoptosis, and thus the p14/DAP kinase/HDM2/p53/Apaf-1 pathway, is potentially important in carcinogenesis. Chronic lymphocytic leukemia (CLL), uncommon in the Chinese, is a disease characterized by impaired apoptosis, of the neoplastic lymphocytes. Hypermethylation of p14, DAP kinase and Apaf-1 was studied by methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) alleles in 50 diagnostic marrow samples from patients with CLL. Chinese CLL patients had an indolent course similar to Caucasians with median overall survival (OS) of 96 months, which was adversely affected by advanced Rai stage (projected 5-year OS = 72% and 39% for Rai ≤ 2 and Rai > 2; P = 0.01). DAP kinase was methylated in 18 (36%) patients while p14 and Apaf-1 were completely unmethylated in all the primary CLL samples. There was no correlation between DAP kinase hypermethylation and age, sex, poor-risk karyotype, lymphocyte count and Rai stage at diagnosis. Projected OS for patients with and without DAP kinase hypermethylation were 59 and 57% (P = 0.91). DAP kinase, but not p14 and Apaf-1, of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway is frequently hypermethylated in CLL, but not of prognostic significance. Moreover Chinese patients with CLL share a similarly indolent clinical course, and this is the first comprehensive study on p14, DAP kinase and Apaf-1 hypermethylation in CLL.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Reference
Chan EC, Lam SY, Tsang KW, Lam B, Ho JC, Fu KH, Lam WK, Kwong YL (2002) Aberrant promoter methylation in Chinese patients with non-small cell lung cancer: patterns in primary tumors and potential diagnostic application in bronchoalevolar lavage. Clin Cancer Res 8:3741–3746
Chim CS, Tam CY, Liang R, Kwong YL (2001a) Methylation of p15 and p16 genes in adult acute leukemia: lack of prognostic significance. Cancer 91:2222–2229
Chim CS, Liang R, Tam C, Kwong YL (2001b) p15 and P16 promoter methylation in acute promyelocytic leukemia. J Clin Oncol 19:2033–2040
Chim CS, Liang R, Kwong YL (2002) Gene promoter hypermethylation in hematologic malignancies. Hematol Oncol 20: 167–176
Chim CS, Fung TK, Cheung J, Liang R Kwong YL (2004a) SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 103:4630–4635
Chim CS, Kwong YL, Fung TK, Liang R (2004b) Methylation profiling in multiple myeloma. Leuk Res 28:379–385
Chim CS, Fung TK, Wong KF, Lau JS, Law M, Liang R (2005a) Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor (CKI) in chronic lymphocytic leukemia (CLL) in Chinese. J Clin Pathol (in press)
Chim CS, Wong AS, Pang A, Chu P, Lau JS, Wong KF, Kwong YL (2005b) Aberrant promoter methylation of the retinoic acid receptor alpha gene in acute promyelocytic leukemia. Leukemia (in press)
Chim CS, Fung TK, Wong KF, Lau JS, Liang R (2006) Infrequent Wnt inhibitory factor-1 (Wif-1) methylation in Chronic Lymphocytic Leukemia. Leukemia Res (in press)
Christiansen DH, Andersen MK, Pedersen-Bjergaard J (2003) Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 17:1813–1819
Drexler HG (1998) Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leuKemia-lymphoma cells. Leukemia 12:845–859
Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, Herman JG (2000) Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 60:129–133
Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancers. Can Res 61: 3225–3229
Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–6
Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054
Juliusson G, Merup M (1998) Cytogenetics in chronic lymphocytic leukemia. Semin Oncol 25:19–26
Katzenellenbogen RA, Baylin SB, Herman JG (1999) Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 93:4347–4353
Keating MJ, Chiorazzi N, Messmer B, Damle RN, Allen SL, Rai KR, Ferrarini M, Kipps TJ (2003) Biology and treatment of chronic lymphocytic leukemia. In Hematology (Am Soc Hematol Educ Program). pp 153–175
Kwong YL, Wong KF, Chan LC, Liang RHS, Chan JKC, Wei D, Chiu EKW, Chan CH, Todd D, Chan TK (1994) The spectrum of chronic lymphoproliferative disorders in Chinese people: an analysis of 64 cases. Cancer 74:174–181
Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432:307–315
Ma SY, Au WY, Chim CS, Lie AK, Lam CC, Tse E, Leung AY, Liang R, Kwong YL (2004) Fludarabine, mitoxantrone and dexamethasone in the treatment of indolent B- and T-cell lymphoid malignancies in Chinese patients. Br J Haematol 124:754–761
Muller-Hermelink HK, Catovsky D, Monstserrat E, Harris NL (2001) Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) Pathology and genetics of tumours of the haematopoietic and lymphoid tissues world health organization classification of tumours, International Agency for Research on Cancer, Lyon pp 127–130
Nagy E, Beck Z, Kiss A, Csoma E, Telek B, Konya J, Olah E, Rak K, Toth FD (2003) Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase. Eur J Cancer 39:2298–2305
Parker SL, Tong T, Bolden S, Wingo PA (1997) Cancer statistics. Ca Cancer J Clin 47:5–27
Peller S, Rotter V (2003) TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum Mutat 21:277–284
Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A (2001) DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol 3:1–7
Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A (2004) Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood 104:2492–2498
Sherr CJ (2001) The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2:731–737
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409:207–211
Taniguchi T, Chikatsu N, Takahashi S, Fujita A, Uchimaru K, Asano S, Fujita T, Motokura T (1999) Expression of p16INK4A and p14ARF in hematological malignancies. Leukemia 13:1760–1769
Winkler D, Schneider C, Kröber A, Pasqualucci L, Lichter P, Döhner H, Stilgenbauer S (2005) Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL). Leukemia 19:1211–1215
Wong KF, Chan JKC (1999) Cytogenetic abnormalities in chronic B-cell lymphoproliferative disorders in Chinese. Cancer Genet Cytogenet 111:55–60
Acknowledgment
We thank Professor LC Chan and Dr Clarence Lam in the University Department of Pathology, Queen Mary Hospital, for pathological diagnoses, and Miss YY Chan and her team for the provision of excellent nursing care.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chim, C.S., Fung, T.K., Wong, K.F. et al. Frequent DAP kinase but not p14 or Apaf-1 hypermethylation in B-cell chronic lymphocytic leukemia. J Hum Genet 51, 832–838 (2006). https://doi.org/10.1007/s10038-006-0029-x
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-006-0029-x
Keywords
This article is cited by
-
Methylation of miR124a-1, miR124a-2, and miR124a-3 in Hodgkin lymphoma
Tumor Biology (2015)
-
Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia
Journal of Translational Medicine (2014)
-
Epigenetic inactivation of the MIR129-2 in hematological malignancies
Journal of Hematology & Oncology (2013)
-
Epigenetic inactivation of miR-9 family microRNAs in chronic lymphocytic leukemia - implications on constitutive activation of NFκB pathway
Molecular Cancer (2013)
-
Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing
BMC Genomics (2007)
