Abstract
Hck and Lyn are required in Philadelphia chromosome (Ph) positive acute lymphocytic leukemia (ALL). Here, we present evidence that the promoter CpG island of Hck, but not of Lyn, is aberrantly methylated in leukemia. Hck promoter DNA methylation was detected in 13 out of 23 (56.5%) hematopoietic and eight out of 10 (80%) non-hematopoietic cell lines, but not in normal controls. Treatment with 5-aza-2′-deoxycytidine induced demethylation and restoration of Hck mRNA and protein expression. Hck methylation (⩾15%) was detected in nine out of 44 (20%) patients with Ph negative ALL, and in one out 16 (6%) patients with Ph positive ALL, but not in patients with AML or chronic myelogenous leukemia. In this subset of patients, low levels of Hck methylation (10–15%) were observed in 26–30% of patients. Lyn methylation was observed in three out of 28 (10.7%) cell lines, but only in one out of 71 (1.4%) patients. Patients with Ph negative ALL and Hck methylation had a poorer prognosis. These data indicate that Hck may have tumor suppressor properties in BCR-ABL negative leukemia.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sattler M, Griffin JD . Molecular mechanisms of transformation by the BCR-ABL oncogene. Semin Hematol 2003; 40 (Suppl 2): 4–10.
Stanglmaier M, Warmuth M, Kleinlein I, Reis S, Hallek M . The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains. Leukemia 2003; 17: 283–289.
Roginskaya V, Zuo S, Caudell E, Nambudiri G, Kraker AJ, Corey SJ . Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth. Leukemia 1999; 13: 855–861.
Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.
Abram CL, Courtneidge SA . Src family tyrosine kinases and growth factor signaling. Exp Cell Res 2000; 254: 1–13.
Danhauser-Riedl S, Warmuth M, Druker BJ, Emmerich B, Hallek M . Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res 1996; 56: 3589–3596.
Warmuth M, Bergmann M, Priess A, Hauslmann K, Emmerich B, Hallek M . The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem 1997; 272: 33260–33270.
Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 2002; 21: 5766–5774.
Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004; 36: 453–461.
Shivakrupa R, Radha V, Sudhakar C, Swarup G . Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain. J Biol Chem 2003; 278: 52188–52194.
Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G . Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk Res 2005; 29: 739–748.
Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S et al. Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 2003; 101: 4131–4136.
Xiong Z, Laird PW . COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res 1997; 25: 2532–2534.
Tien HF, Tang JH, Tsay W, Liu MC, Lee FY, Wang CH et al. Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation. Br J Haematol 2001; 112: 148–154.
Jones PA, Baylin SB . The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–428.
Robertson KD, Wolffe AP . DNA methylation in health and disease. Nat Rev Genet 2000; 1: 11–19.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96: 8681–8686.
Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G et al. Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood 2004; 104: 2492–2498.
Melki JR, Vincent PC, Clark SJ . Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 1999; 59: 3730–3740.
Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP . Methylation profiling in acute myeloid leukemia. Blood 2001; 97: 2823–2829.
Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM et al. DNA methylation of multiple promoter-associated CpG Islands in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 2217–2224.
Garcia-Manero G, Bueso-Ramos C, Daniel J, Williamson J, Kantarjian HM, Issa JP . DNA methylation patterns at relapse in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 1897–1903.
Nguyen TT, Mohrbacher AF, Tsai YC, Groffen J, Heisterkamp N, Nichols PW et al. Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Blood 2000; 95: 2990–2992.
Issa JP, Kantarjian H, Mohan A, O'Brien S, Cortes J, Pierce S et al. Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance [see comments]. Blood 1999; 93: 2075–2080.
Ben-Yehuda D, Krichevsky S, Rachmilewitz EA, Avraham A, Palumbo GA, Frassoni F et al. Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia. Blood 1997; 90: 4918–4923.
Asimakopoulos FA, Shteper PJ, Krichevsky S, Fibach E, Polliack A, Rachmilewitz E et al. ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia. Blood 1999; 94: 2452–2460.
Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 2005; 23: 3948–3956.
Acknowledgements
This work was funded in part by Grants CA100067 and CA105771 from the NCI, and the University of Texas MD Anderson Cancer Center's Physician-Scientist Program Award funded by the Commonwealth Cancer Foundation for Research (G G-M). We thank Claritza Santos-Malave, a visiting student from the University of Puerto Rico, for technical assistance, and to Drs N Donato and M Beran for sharing cell lines. DNA sequencing was performed at a core facility at the University of Texas MD Anderson Cancer funded by Core Grant CA16672.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
Supplementary information
Rights and permissions
About this article
Cite this article
Hoshino, K., Quintás-Cardama, A., Yang, H. et al. Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia. Leukemia 21, 906–911 (2007). https://doi.org/10.1038/sj.leu.2404615
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404615
Keywords
This article is cited by
-
Effects of post-transplant maintenance therapy with decitabine prophylaxis on the relapse for acute lymphoblastic leukemia
Bone Marrow Transplantation (2023)
-
Identification of the Shared Gene Signatures of HCK, NOG, RNF125 and Biological Mechanism in Pediatric Acute Lymphoblastic Leukaemia and Pediatric Sepsis
Molecular Biotechnology (2023)
-
Successful induction therapy with decitabine in refractory childhood acute lymphoblastic leukemia
Leukemia (2009)
-
Opposite expression pattern of Src kinase Lyn in acute and chronic haematological malignancies
Annals of Hematology (2009)
-
A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis
Leukemia (2008)