The acquisition of complex karyotypes is related to the progression of chronic lymphocytic leukemia (CLL) and patients with this condition have a poor prognosis. Despite recent advances in the classification of prognosis in CLL patients, understanding of the molecular mechanisms that lead to genomic instability and progression of this disease remains inadequate. Interestingly, dysregulated expression of KDM4 members is involved in the progression of several cancer types and plays a role in the DNA damage response; however, the gene expression profile and the importance of KDM4 members in CLL are still unknown. Here, we assessed the gene expression profile of KDM4A, KDM4B, and KDM4C in 59 CLL samples and investigated whether these histone demethylases have any influence on the prognostic markers of this leukemia. KDM4A gene expression was higher in CLL patients as compared with control samples. In contrast, CLL samples showed decreased levels of the KDM4B transcript in relation to control cases, and no difference was detected in KDM4C expression. Furthermore, patients with positive expression of ZAP-70 had lower expression of KDM4B and KDM4C as compared with ZAP-70-negative patients. More importantly, patients with low expression of these histone demethylases had higher leukemic cell numbers and displayed adverse cytogenetic findings and the acquisition of a complex karyotype. The present data clearly show that the expression of KDM4 members is dysregulated in CLL and impact the prognosis of this leukemia. These findings are useful for a better understanding of the impact of epigenetics on CLL progression.
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This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and Fundação de Amparo à Pesquisa do Distrito Federal (FAPDF).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval and informed consent
The study was approved by the Ethical Committee of the Medical School Hospital of Ribeirão Preto, University of São Paulo, Brazil, and samples were collected after informed consent was obtained from patients and health donors.
Roos-Weil D, Nguyen-Khac F, Bernard OA. Chronic lymphocytic leukemia: time to go past genomics? Am J Hematol. 2016;91:518–28.CrossRefGoogle Scholar
Barrientos JC. Sequencing of chronic lymphocytic leukemia therapies. Hematol Am Soc Hematol Educ Progr. 2016;2016:128–36.CrossRefGoogle Scholar
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6.CrossRefGoogle Scholar
Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R, et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006;107:742–51.CrossRefGoogle Scholar
Højfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12:917–30.CrossRefGoogle Scholar
Labbé RM, Holowatyj A, Yang Z-Q. Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. Am J Transl Res. 2013;6:1–15.PubMedPubMedCentralGoogle Scholar
Berry WL, Janknecht R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 2013;73:2936–42.CrossRefGoogle Scholar
Young LC, McDonald DW, Hendzel MJ. Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following γ-irradiation. J Biol Chem. 2013;288:21376–88.CrossRefGoogle Scholar
Khoury-Haddad H, Guttmann-Raviv N, Ipenberg I, Huggins D, Jeyasekharan AD, Ayoub N. PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair. Proc Natl Acad Sci USA. 2014;111:E728–37.CrossRefGoogle Scholar
Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia. 1994;8:1640–5.PubMedGoogle Scholar
Carvalho Alves-Silva J, do Amaral Rabello D, Oliveira Bravo M, Lucena-Araujo A, Madureira de Oliveira D, Morato de Oliveira F, et al. Aberrant levels of SUV39H1 and SUV39H2 methyltransferase are associated with genomic instability in chronic lymphocytic leukemia. Environ Mol Mutagen. 2017;58:654–61.CrossRefGoogle Scholar
Nabhan C, Raca G, Wang YL. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era. JAMA Oncol. 2015;1:965–74.CrossRefGoogle Scholar
Kogure M, Takawa M, Cho H-S, Toyokawa G, Hayashi K, Tsunoda T, et al. Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition. Cancer Lett. 2013;336:76–84.CrossRefGoogle Scholar
Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell. 2013;154:541–55.CrossRefGoogle Scholar
Young LC, Hendzel MJ. The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression. Biochem Cell Biol. 2013;91:369–77.CrossRefGoogle Scholar
Ouillette P, Collins R, Shakhan S, Li J, Peres E, Kujawski L, et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood. 2011;118:3051–61.CrossRefGoogle Scholar
Awwad SW, Ayoub N. Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway. Biol Open. 2015;4:498–504.CrossRefGoogle Scholar
Ishimura A, Terashima M, Kimura H, Akagi K, Suzuki Y, Sugano S, et al. Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene. Biochem Biophys Res Commun. 2009;389:366–71.CrossRefGoogle Scholar