Aberrant DNA methylation in adult B-cell acute lymphoblastic leukemia and the therapeutic potential of hypomethylating agents

Abstract

Aberrant DNA methylation is prevalent in acute lymphoblastic leukemia (ALL), particularly in adult cases, where abnormally high methylation levels correlate significantly with patient age and survival outcomes. Indeed, older patients are more frequently classified into high-risk subgroups due to gene dysfunction driven by aberrant methylation, highlighting its prognostic value. Thus, DNA methylation serves as a valuable prognostic marker for adult patients and supports the therapeutic use of hypomethylating agents (HMAs). In this review, we summarize the latest insights into DNA methylation and its regulation in the context of adult B-ALL and outline the potential clinical application of HMAs for adult patients.

Keywords

Adult B-cell acute lymphoblastic leukemia / DNA methylation / Epigenetic regulators / Hypomethylating agents

References

Abid MB, Estrada-Merly N, Zhang MJ, Chen K, Bredeson C, Allan D, Sabloff M, Marks DI, Litzow M, Hourigan C, Kebriaei P, Saber W. Younger matched unrelated donors confer decreased relapse risk compared to older sibling donors in older patients with B cell acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation. Transplant Cell Ther, 2023, 29(10):611-618

Agirre X, Vilas-Zornoza A, Jiménez-Velasco A, Martin-Subero JI, Cordeu L, Gárate L, San José-Eneriz E, Abizanda G, Rodríguez-Otero P, Fortes P, Rifón J, Bandrés E, Calasanz MJ, Martín V, Heiniger A, Torres A, Siebert R, Román-Gomez J, Prósper F. Epigenetic Silencing of the tumor suppressor MicroRNA Has-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Research, 2009, 69(10):4443-4453

Agrawal S, Unterberg M, Koschmieder S, zur Stadt U, Brunnberg U, Verbeek W, Büchner T, Berdel WE, Serve H, Müller-Tidow C. DNA methylation of tumor suppressor genes in clinical remission predicts the relapse risk in acute myeloid leukemia. Cancer Research, 2007, 67(3):1370-1377

Andrews S, Krueger C, Mellado-Lopez M, Hemberger M, Dean W, Perez-Garcia V, Hanna CW. Mechanisms and function of de Novo DNA methylation in placental development reveals an essential role for DNMT3B. Nature Communications, 2023, 14(1):371

Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bücklein VL, Bonig H, Cario G, Einsele H, Holtick U, Koenecke C, Bakhtiar S, Künkele A, Meisel R, Müller F, Müller I, Penack O, Rettinger E, Sauer MG, et al. CD19 CAR T cells are an effective therapy for posttransplant relapse in. patients with B-lineage ALL: real-world data from Germany. Blood Adv, 2023, 7(11):2436-2448

Bahari G, Hashemi M, Naderi M, Taheri M. TET2 promoter DNA methylation and expression in childhood acute lymphoblastic leukemia. Asian Pacific Journal of Cancer Prevention, 2016, 17(8):3959-3962.

Bassan R, Fumagalli M, Chiaretti S, Audisio E, Cascavilla N, Paolini S, Delia M, Cerqui E, Micò C, Fabbiano F, Canichella M, Scattolin AM, Perfetti P, Paoloni F, Iodice M, Vitale A, Della Starza I, Fazi P, Vignetti M, Foà R. Phase II trial with sequential Clofarabine and cyclophosphamide for refractory and relapsed Philadelphia-negative adult acute lymphoblastic leukemia. Results of the GIMEMA LAL 1610 protocol. Leukaemia & Lymphoma, 2019, 60(14):3482-3492

Batsché E, Yi J, Mauger O, Kornobis E, Hopkins B, Hanmer-Lloyd C, Muchardt C. CD44 alternative splicing senses intragenic DNA methylation N in tumors via direct and indirect mechanisms. Nucleic Acids Research, 2021, 49(11):6213-6237

Bensberg M, Rundquist O, Selimović A, Lagerwall C, Benson M, Gustafsson M, Vogt H, Lentini A, Nestor CE. TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A, 2021, 118(34):e2110758118

Benton CB, Thomas DA, Yang H, Ravandi F, Rytting M, O’Brien S, Franklin AR, Borthakur G, Dara S, Kwari M, Pierce SR, Jabbour E, Kantarjian H, Garcia-Manero G. Safety and clinical activity of 5-aza-2’-deoxycytidine (decitabine). With or Without Hyper-CVAD in relapsed/refractory acute lymphocytic leukaemia. British Journal of Haematology, 2014, 167(3):356-365

Bhootra S, Jill N, Shanmugam G, Rakshit S, Sarkar K. DNA methylation and cancer: Transcriptional regulation, prognostic, and therapeutic perspective. Medical Oncology, 2023, 40(2):71

Bond J, Touzart A, Leprêtre S, Graux C, Bargetzi M, Lhermitte L, Hypolite G, Leguay T, Hicheri Y, Guillerm G, Bilger K, Lhéritier V, Hunault M, Huguet F, Chalandon Y, Ifrah N, Macintyre E, Dombret H, et al. DNMT3A mutation is associated with increased age and adverse outcome in adult T-cell acute lymphoblastic leukemia. Haematologica, 2019, 104(8):1617-1625

Borssén M, Nordlund J, Haider Z, Landfors M, Larsson P, Kanerva J, Schmiegelow K, Flaegstad T, Jónsson ÓG, Frost BM, Palle J, Forestier E, Heyman M, Hultdin M, Lönnerholm G, Degerman S. DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clin Epigenetics, 2018, 5: 31

Božić T, Frobel J, Raic A, Ticconi F, Kuo CC, Heilmann-Heimbach S, Goecke TW, Zenke M, Jost E, Costa IG, Wagner W. Variants of DNMT3A cause transcript-specific DNA methylation patterns and affect hematopoiesis. Life Sci Alliance, 2018, 1(6):e201800153

Brakensiek K, Länger F, Kreipe H, Lehmann U. Absence of p21(CIP 1), p27(KIP 1) and P 57(KIP 2) methylation in MDS and AML. Leukemia Research, 2005, 29(11):1357-1360

Brunetti L, Gundry MC, Goodell MA. DNMT3A in leukemia. Cold Spring Harb Perspect Med, 2017, 7(2):a030320

Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernández-Piqueras J, Malumbres M. Genetic and epigenetic Silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell, 2008, 13(6):496-506

Bueso-Ramos C, Xu Y, McDonnell TJ, Brisbay S, Pierce S, Kantarjian H, Rosner G, Garcia-Manero G. Protein expression of a triad of frequently methylated genes, p73, p57Kip2, and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status. Journal of Clinical Oncology, 2005, 23(17):3932-3939

Burke MJ, Lamba JK, Pounds S, Cao X, Ghodke-Puranik Y, Lindgren BR, Weigel BJ, Verneris MR, Miller JS. A therapeutic trial of decitabine and Vorinostat in combination with. Chemotherapy for relapsed/refractory acute lymphoblastic leukemia. American Journal of Hematology, 2014, 89(9):889-895

Canalli AA, Yang H, Jeha S, Hoshino K, Sanchez-Gonzalez B, Brandt M, Pierce S, Kantarjian H, Issa JP, Garcia-Manero G. Aberrant DNA methylation of a cell cycle regulatory Patiwat composed of P73, P15 and P57KIP2 is a rare event in children with acute lymphocytic leukemia. Leukemia Research, 2005, 29(8):881-885

Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, Karp JE. Phase 1 study of the histone deacetylase inhibitor entinostat plus Clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia. Leukemia Research, 2021, 110: 106707

Caserta C, Nucera S, Barcella M, Fazio G, Naldini MM, Pagani R, Pavesi F, Desantis G, Zonari E, D’Angiò M, Capasso P, Lombardo A, Merelli I, Spinelli O, Rambaldi A, Ciceri F, Silvestri D, Valsecchi MG, Biondi A, et al. miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease. Leukemia, 2023, 37(10):1994-2005

Li CHEN, Cong-cong ZHANG, Qing-shan LI, Xiao-hui SUO, Hui-juan JI Hong-feng. Methylation of DNMT1 and SFRP1 gene in bone marrow and its correlation with clinicophathological features and prognosis in patients with AML and ALL. J Mod Lab Med, 2022, 37(6):7-13

Chen Z, Zhou K, Xue J, Small A, Xiao G, Nguyen LXT, Zhang Z, Prince E, Weng H, Huang H, Zhao Z, Qing Y, Shen C, Li W, Han L, Tan B, Su R, Qin H, Li Y, et al. Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target. In B cell acute lymphoblastic leukemia. Science Translational Medicine, 2023, 15(689):eabq8513

Corn, P. G., Kuerbitz, S. J., van Noesel, M. M., Esteller, M., Compitello, N., Baylin, S. B., & Herman, J. G. (1999). Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG Island methylation. Cancer Research. 59(14):3352–3356.

Coustan-Smith E, Song G, Clark C, Key L, Liu P, Mehrpooya M, Stow P, Su X, Shurtleff S, Pui CH, Downing JR, Campana D. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood, 2011, 117(23):6267-6276

Creasey T, Barretta E, Ryan SL, Butler E, Kirkwood AA, Leongamornlert D, Papaemmanuil E, Patrick P, Clifton-Hadley L, Patel B, Menne T, McMillan AK, Harrison CJ, Rowntree CJ, Morley N, Marks DI, Fielding AK, Moorman AV. Genetic and genomic Analysis of acute lymphoblastic leukemia in. older adults reveals a distinct profile of abnormalities: Analysis of 210 patients from the UKALL14 and UKALL60 + clinical trials. Haematologica, 2022, 107(9):2051-2063

Cui JK, Xiao Y, You Y, Shi W, Li Q, Luo Y, Jiang L, Zhong ZD. Decitabine for relapsed acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. J Huazhong Univ Sci Technolog Med Sci, 2017, 37(5):693-698

DiNardo CD, Gharibyan V, Yang H, Wei Y, Pierce S, Kantarjian HM, Garcia-Manero G, Rytting M. Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia. American Journal of Hematology, 2013, 88(9):784-789

Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen H, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV Evans WE. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nature Medicine, 2011, 17(10):1298-1303

Duymich CE, Charlet J, Yang X, Jones PA, Liang G. DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. Nature Communications, 2016, 28: 11453

Fan J, Lu R, Zhu J, Guo X, Wan D, Xie X, Cao W, Zhang Y, Zhao H, Li Y, Guo R, Jiang Z, Song Y, He F, Guo R. Effects of post-transplant maintenance therapy with decitabine prophylaxis on the relapse for acute lymphoblastic leukemia. Bone Marrow Transplantation, 2023, 58(6):687-695

Forsterová K, Votavová H, Schwarz J, Karban J, Stuka C, Trněný MF. Advanced Rai stage in patients with chronic lymphocytic leukaemia correlates with simultaneous hypermethylation of plural tumour suppressor genes. Folia Biologica (Praha), 2010, 56(4):158-164.

Fu HY, Wu DS, Zhou HR, Shen JZ. CpG Island methylator phenotype and its relationship with prognosis in adult acute leukemia patients. Hematology, 2014, 19(6):329-337

Fulci V, Colombo T, Chiaretti S, Messina M, Citarella F, Tavolaro S, Guarini A, Foà R, Macino G. Characterization of B- and T-lineage acute lymphoblastic leukemia by integrated analysis of MicroRNA and mRNA expression profile. Genes Chromosomes & Cancer, 2009, 48(12):1069-1082

Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, Issa JP. DNA methylation of multiple promoter-associated CpG Islands in adult acute lymphocytic leukemia. Clinical Cancer Research, 2002, 8(7):2217-2224.

Garcia-Manero G, Jeha S, Daniel J, Williamson J, Albitar M, Kantarjian HM, Issa JP. Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer, 2003, 97(3):695-702

Garcia-Prieto CA, Villanueva L, Bueno-Costa A, Davalos V, González-Navarro EA, Juan M, Urbano-Ispizua Á, Delgado J, Ortiz-Maldonado V, Del Bufalo F, Locatelli F, Quintarelli C, Sinibaldi M, Soler M, Castro de Moura M, Ferrer G, Urdinguio RG, Fernandez AF, Fraga MF, et al. Epigenetic profiling and response to CD19 chimeric antigen receptor T-cell therapy in B-cell malignancies. Journal of the National Cancer Institute, 2022, 114(3):436-445

Gautrey HE, van Otterdijk SD, Cordell HJ Newcastle 85 + Study Core Team Mathers JC, Strathdee G. DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells. The Faseb Journal, 2014, 28(7):3261-3272

Geng H, Brennan S, Milne TA, Chen WY, Li Y, Hurtz C, Kweon SM, Zickl L, Shojaee S, Neuberg D, Huang C, Biswas D, Xin Y, Racevskis J, Ketterling RP, Luger SM, Lazarus H, Tallman MS, Rowe JM, et al. Intergrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic keukemia. Cancer Discovery, 2012, 2(11):1004-1023

Gökbuget N, Boissel N, Chiaretti S, Dombret H, Doubek M, Fielding A, Foà R, Giebel S, Hoelzer D, Hunault M, Marks DI, Martinelli G, Ottmann O, Rijneveld A, Rousselot P, Ribera J, Bassan R. Management of ALL in adults: 2024 ELN recommendations from a European expert panel. Blood, 2024, 143(19):1903-1930

Gong X, Fang Q, Gu R, Qiu S, Liu K, Lin D, Zhou C, Zhang G, Gong B, Liu Y, Li Y, Liu B, Wang Y, Wei H, Mi Y, Wang J. A pediatric-inspired regimen for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: A prospective study from China. Haematologica, 2024, 109(10):3146-3156

Gossai N, Verneris MR, Karras NA, Gorman MF, Patel NJ, Burke MJ. A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD). Bone Marrow Transplantation, 2014, 49(3):440-442

Gu X, Tohme R, Tomlinson B, Sakre N, Hasipek M, Durkin L, Schuerger C, Grabowski D, Zidan AM, Radivoyevitch T, Hong C, Carraway H, Hamilton B, Sobecks R, Patel B, Jha BK, His ED, Maciejewski J, Saunthararajah Y. Decitabine- and 5-azacytiding resistance emerges from adaptive responses of the pyrimidine metabolism network. Leukemia, 2021, 35(4):1023-1036

Gutiérrez MI, Siraj AK, Bhargava M, Ozbek U, Banavali S, Chaudhary MA, El Solh H, Bhatia K. Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup. Leukemia, 2003, 17(9):1845-1850

Gutiérrez MI, Siraj AK, Ibrahim MM, Hussain A, Bhatia K. Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes. American Journal of Hematology, 2005, 80(2):158-160

Haider Z, Larsson P, Landfors M, Köhn L, Schmiegelow K, Flaegstad T, Kanerva J, Heyman M, Hultdin M, Degerman S. An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression. Cancer Medicine, 2019, 8(1):311-324

Hao Z, Fei Y, Chen J, Huang S, Wang L, Yu Y, Bian M, Si Y, Zhang X, Yang X, Zhang B, Wan Y, Zhang Y, Lin G. Combination of venetoclax and Azacytidine in relapsed/refractory acute B-cell lymphoblastic leukemia: A case series from A single center. Hematology, 2024, 29(1):2344998

HessonLB, DunwellTL, CooperWN, CatchpooleD, BriniAT, ChiaramonteR, GriffithsM, ChalmersAD, MaherER, & LatifF (2009). The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Molecular Cancer, 1(8), 42. https://doi.org/10.1186/1476-4598-8-42

Hiller JK, Hiller JK, Schmoor C, Gaidzik VI, Schmidt-Salzmann C, Yalcin A, Abdelkarim M, Blagitko-Dorfs N, Döhner K, Bullinger L, Duyster J, Lübbert M, Hackanson B. Evaluating the impact of genetic and epigenetic aberrations on survival and response in acute myeloid leukemia patients receiving epigenetic therapy. Annals of Hematology, 2017, 96(4):559-565

Hoang NM, Rui L. DNA methyltransferases in hematological malignancies. J Genet Genomics, 2020, 47(7):361-372

Horst HA, Zugmaier G, Martinelli G, Mergen N, Velasco K, Zaman F, Kantarjian H. CD19-negative relapse in adult patients with relapsed/refractory B-cell. Precursor acute lymphoblastic leukemia following treatment with blinatumomab-a post hoc analysis. American Journal of Hematology, 2023, 98(8):E222-E225

Hoshino K, Asou N, Okubo T, Suzushima H, Kiyokawa T, Kawano F, Mitsuya H. The absence of the p15INK4B gene alterations in adult patients with precursor acute lymphoblastic leukaemia is a favourable prognostic factor. British Journal of Haematology, 2002, 117(3):531-540

Hosseini-Alghaderi S, Baron M. Notch3 in development, health and disease. Biomolecules, 2020, 10(3):485

Hou T, Gao F, Wang Q, Zhao J, Flagg T, Zhang Y, Deng X. Bcl2 impedes DNA mismatch repair by directly regulating the hMSH2-hMSH6 heterodimeric complex. Journal of Biological Chemistry, 2007, 282(12):9279-9287

Huang M, Inukai T, Miyake K, Tanaka Y, Kagami K, Abe M, Goto H, Minegishi M, Iwamoto S, Sugihara E, Watanabe A, Somazu S, Shinohara T, Oshiro H, Akahane K, Goi K, Sugita K. Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low Deoxycytidine kinase expression. Cancer Medicine, 2018, 7(4):1297-1316

Huang X, Hao Q, Fang Q, Zhang P, Wei H, Wang Y, Wang J, Mi Y. Correlation between methylation level of the SLC19A1 promoter region and methotrexate metabolism in adult acute lymphoblastic leukemia. Pharmacogenomics, 2023, 24(5):261-268

Huguet F, Leguay T, Raffoux E, Rousselot P, Vey N, Pigneux A, Ifrah N, Dombret H. Clofarabine for The treatment of adult acute lymphoid leukemia: The group for research on adult acute lymphoblastic leukemia intergroup. Leukaemia & Lymphoma, 2015, 56(4):847-857

Hussan SS, Ali MS, Fatima M, Altaf M, Sadaf S. Epigenetically dysregulated NOTCH-Delta-HES signaling cascade can serve as a subtype classifier for acute lymphoblastic leukemia. Annals of Hematology, 2024, 103(2):511-523

Iacobucci I, Iraci N, Messina M, Lonetti A, Chiaretti S, Valli E, Ferrari A, Papayannidis C, Paoloni F, Vitale A, Storlazzi CT, Ottaviani E, Guadagnuolo V, Durante S, Vignetti M, Soverini S, Pane F, Foà R, Baccarani M, et al. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia. PLoS One, 2012, 7(7):e40934

Jabbour E, Short NJ, Jain N, Haddad FG, Welch MA, Ravandi F, Kantarjian H. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. Journal of Hematology & Oncology, 2023, 16(1):22

Jiménez-Velasco A, Román-Gómez J, Agirre X, Barrios M, Navarro G, Vázquez I, Prósper F, Torres A, Heiniger A. Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia, 2005, 19(12):2347-2350

Kaufman-Szymczyk A, Lubecka K. The effects of Clofarabine in ALL Inhibition through DNA methylation regulation. Acta Biochimica Polonica, 2020, 67(1):65-72

Kayser S, Sartor C, Luskin MR, Webster J, Giglio F, Panitz N, Brunner AM, Fante M, Lutz C, Wolff D, Ho AD, Levis MJ, Schlenk RF, Papayannidis C. Outcome of relapsed or refractory acute B-lymphoblastic leukemia patients and BCR-ABL-positive blast cell crisis of B-lymphoid lineage with extramedullary disease receiving inotuzumab Ozogamicin. Haematologica, 2022, 107(9):2064-2071

Kilikevicius A, Meister G, Corey DR. Reexamining assumptions about miRNA-guided gene Silencing. Nucleic Acids Research, 2022, 50(2):617-634

Kim M, Yim SH, Cho NS, Kang SH, Ko DH, Oh B, Kim TY, Min HJ, She CJ, Kang HJ, Shin HY, Ahn HS, Yoon SS, Kim BK, Shin HR, Han KS, Cho HI, Lee DS. Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is A poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: A comparative deletion and hypermethylation study. Cancer Genetics and Cytogenetics, 2009, 195(1):59-65

Kim MS, Kim YR, Yoo NJ, Lee SH. Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers. APMIS, 2013, 121(2):85-94

Kuang SQ, Fang Z, Zweidler-McKay PA, Yang H, Wei Y, Gonzalez-Cervantes EA, Boumber Y, Garcia-Manero G. Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia. PLoS One, 2013, 8(4):e61807

Kubota H, Ueno H, Tasaka K, Isobe T, Saida S, Kato I, Umeda K, Hiwatari M, Hasegawa D, Imamura T, Kakiuchi N, Nannya Y, Ogawa S, Hiramatsu H, Takita J. RNA-seq-based MiRNA signature as an independent predictor of relapse in pediatric B-cell acute lymphoblastic leukemia. Blood Adv, 2024, 8(5):1258-1271

Lev Maor G, Yearim A, Ast G. The alternative role of DNA methylation in splicing. Regulation. Trends in Genetics, 2015, 31(5):274-280

Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, Liu YF, Qian MX, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, et al. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A, 2018, 115(50):E11711-E11720

Li S, Xue L, Wang M, Qiang P, Xu H, Zhang X, Kang W, You F, Xu H, Wang Y, Liu X, Yang L, Wang X. Decitabine enhances cytotoxic effect of T cells with an anti-CD19 chimeric antigen receptor in treatment of lymphoma. Onco Targets Ther, 2019, 12:12: 5627-5638

Li B, Brady SW, Ma X, Shen S, Zhang Y, Li Y, Szlachta K, Dong L, Liu Y, Yang F, Wang N, Flasch DA, Myers MA, Mulder HL, Ding L, Liu Y, Tian L, Hagiwara K, Xu K, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood, 2020, 135(1):41-55

Li D, Yuan Y, Meng C, Lin Z, Zhao M, Shi L, Li M, Ye D, Cai Y, He X, Ye H, Zhou S, Zhou H, Gao S. Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax. Clin Epigenetics, 2024, 16(1):48

Li, W., Liu, S., Wang, C., Cui, L., Zhao, X., Liu, W., Zhang, R., & Li, Z. (2023). DNMT3A low-expression is correlated to poor prognosis in childhood B-ALL and confers resistance to Daunorubicin on leukemic cells. Bmc Cancer 23(1):255. https://doi.org/10.1186/s12885-023-10724-6

Liang EC, Dekker SE, Sabile JMG, Torelli S, Zhang A, Miller K, Shiraz P, Hayes-Lattin B, Leonard JT, Muffly L. Next-generation sequencing-based MRD in adults with ALL undergoing hematopoietic cell transplantation. Blood Adv, 2023, 7(14):3395-3402

Ling ZQ, Zhao Q, Zhou SL, Mao WM. MSH2 promoter hypermethylation in Circulating tumor DNA is a valuable predictor of disease-free survival for patients with esophageal squamous cell carcinoma. European Journal of Surgical Oncology, 2012, 38(4):326-332

Liu M, Taketani T, Li R, Takita J, Taki T, Yang HW, Kawaguchi H, Ida K, Matsuo Y, Hayashi Y. Loss of p73 gene expression in lymphoid leukemia cell lines is associated with hypermethylation. Leukemia Research, 2001, 25(6):441-447

Liu YN, Zhang N, Wu Y, Yang L, Ding XY, Zhou JF, Xiao M. DNMT3A mutation analysis in adult patients with acute lymphoblastic leukemia. J Huazhong Univ Sci Technolog Med Sci, 2015, 35(3):337-342

Liu J, Xie X, Wan D, Cao W, Xing Hm Jiang Z, Sun L, Ding W, Dong Z, Liu Y, Sun H, Guo R. Clinical observation of maintenance treatment with low-dose decitabine after transplantation for patients with high-risk acute lymphoblastic leukemia. J Leukemia & Lymphomas, 2019, 12: 473-478.

Liu J, Jiang ZX, Xie XS, Wan DM, Cao WJ, Wang M, Liu ZZ, Dong ZK, Wang HQ, Lu RQ, Zhang YY, Cheng QQ, Fan JX, Li W, He F, Guo R. Maintenance treatment with Low-Dose decitabine after allogeneic hematopoietic cell transplantation in patients with adult acute lymphoblastic leukemia. Frontiers in Oncology, 2021, 16: 11710545

Ma Y, Dai H, Cui Q, Liu S, Kang L, Lian X, Cui W, Yin J, Liu L, Cai M, Yu L, Wu D, Tang X. Decitabine in combination with fludarabine and cyclophosphamide as a lymphodepletion regimen followed by CD19/CD22 bispecific targeted CAR T-cell therapy significantly improves survival in relapsed/refractory B-ALL patients. Exp Hematol Oncol, 2023, 12(1):36

Mai H, Liu X, Chen Y, Li C, Cao L, Chen X, Chen S, Liu G, Wen F. Hypermethylation of p15 gene associated with an inferior poor long-term outcome in childhood acute lymphoblastic leukemia. Journal of Cancer Research and Clinical Oncology, 2016, 142(2):497-504

Martin V, Agirre X, Jiménez-Velasco A, José-Eneriz ES, Cordeu L, Gárate L, Vilas-Zornoza A, Castillejo JA, Heiniger A, Prósper F, Torres A, Roman-Gomez J. Methylation status of Wnt signaling pathway genes affects the clinical outcome of Philadelphia-positive acute lymphoblastic leukemia. Cancer Science, 2008, 99(9):1865-1868

Martín I, Navarro B, Serrano A, Villamón E, Calabuig M, Solano C, Chaves FJ, Yagüe N, Orts M, Amat P, Fuentes A, Seda E, García F, Hernández-Boluda JC, Tormo M. Impact of clinical features, cytogenetics, genetic mutations, and methylation dynamics of CDKN2B and DLC-1 promoters on treatment response to Azacytidine. Annals of Hematology, 2020, 99(3):527-537

Martín-Palanco V, Rodríguez G, Martín C, Rojas R, Torres A, Román-Gómez J. MicroRNA methylation profile has prognosis impact in acute lymphoblastic leukemia patients undergoing stem cell transplantation. Biology of Blood and Marrow Transplantation, 2011, 17(5):745-748

Matheson EC, Hall AG. Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic leukaemia. Carcinogenesis, 2003, 24(1):31-38

Mattei AL, Bailly N, Meissner A. DNA methylation: A historical perspective. Trends in Genetics, 2022, 38(7):676-707

Menon A, Abd-Aziz N, Khalid K, Poh CL, Naidu R. MiRNA: A promising therapeutic target in cancer. International Journal of Molecular Sciences, 2022, 23(19):11502

Muffly L, Sundaram V, Chen C, Yurkiewicz I, Kuo E, Burnash S, Spiegel JY, Arai S, Frank MJ, Johnston LJ, Lowsky R, Meyer EH, Negrin RS, Rezvani AR, Sidana S, Shiraz P, Shizuru JA, Weng WK, Liedtke M, et al. Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood Adv, 2021, 5(16):3147-3151

Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature, 2008, 453(7191):110-114

Nishioka C, Ikezoe T, Yang J, Nobumoto A, Tsuda M, Yokoyama A. Downregulation of miR-217 correlates with resistance of ph (+) leukemia cells to ABL tyrosine kinase inhibitors. Cancer Science, 2014, 105(3):297-307

Nishiwaki S, Akahoshi Y, Morita-Fujita M, Shimizu H, Uchida N, Ozawa Y, Fukuda T, Tanaka M, Ikegame K, Ota S, Katayama Y, Takahashi S, Kawakita T, Ara T, Onizuka M, Kimura T, Tanaka J, Atsuta Y, Arai Y. Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades. Blood Adv, 2022, 6(15):4558-4569.

Nwabo Kamdje AH, Mosna F, Bifari F, Lisi V, Bassi G, Malpeli G, Ricciardi M, Perbellini O, Scupoli MT, Pizzolo G, Krampera M. Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood, 2011, 118(2):380-389

Poole CJ, Lodh A, Choi JH, Riggelen J. MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL. Epigenetics Chromatin, 2019, 12(1):41

Qian X, Durkin ME, Wang D, Tripathi BK, Olson L, Yang XY, Vass WC, Popescu NC, Lowy DR. Inactivation of the Dlc1 gene cooperates with downregulation of p15INK4b and p16Ink4a, leading to neoplastic transformation and poor prognosis in human cancer. Cancer Research, 2012, 72(22):5900-5911

Rahmani T, Azad M, Chahardouli B, Nasiri H, Vatanmakanian M, Kaviani S. Patterns of DNMT1 promoter methylation in patients with acute lymphoblastic leukemia. Int J Hematol Oncol Stem Cell Res, 2017, 11(3):172-177.

Rahmé R, Benayoun E, Pautas C, Cordonnier C, Wagner-Ballon O, Maury S. Treatment with 5-azacytidine upregulates the expression of CD20 in CD20-negative B cell acute lymphoblastic leukemia: A case report. Experimental Hematology, 2013, 41(6):505-507

Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature, 2000, 404(6781):1003-1007

Richter AM, Pfeifer GP, Dammann RH. The RASSF protiens in cancer; from epigenetic Silencing to functional characterization. Biochimica Et Biophysica Acta, 2009, 1796(2):114-128

Rijneveld AW, van der Holt B, de Weerdt O, Biemond BJ, van de Loosdrecht AA, van der Wagen LE, Bellido M, Gelder M, Velden WJFM, Selleslag D, Lammeren-Venema D, Halkes CJM, Fijnheer R, Havelange V, Sluis GL, Legdeur MC, Deeren D, Gadisseur A, Sinnige HAM, et al. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: The HOVON-100 trial. Blood Adv, 2022, 6(4):1115-1125

Roman-Gomez J, Castillejo JA, Jimenez A, Gonzalez MG, Moreno F, Rodriguez Mdel C, Barrios M, Maldonado J, Torres A. 5’ CpG Island hypermethylation is associated with transcriptional Silencing of the p21 (CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. Blood, 2002, 99(7):2291-2296

Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Garate L, Jose-Eneriz ES, Cordeu L, Barrios M, Prosper F, Heiniger A, Torres A. Promoter hypermethylation and global hypomethylation are independent epigenetic events in lymphoid leukemogenesis with opposing effects on clinical outcome. Leukemia, 2006, 20(8):1445-1448

Roman-Gomez J, Agirre X, Jiménez-Velasco A, Arqueros V, Vilas-Zornoza A, Rodriguez-Otero P, Martin-Subero I, Garate L, Cordeu L, San José-Eneriz E, Martin V, Castillejo JA, Bandrés E, Calasanz MJ, Siebert R, Heiniger A, Torres A, Prosper F. Epigenitic regulation of MicroRNAs in acute lymphoblastic leukemia. Journal of Clinical Oncology, 2009, 27(8):1316-1322

Sala Torra O, Othus M, Williamson DW, Wood B, Kirsch I, Robins H, Beppu L, O’Donnell MR, Forman SJ, Appelbaum FR, Radich JP. Next-Generation sequencing in adult B cell acute lymphoblastic leukemia patients. Biology of Blood and Marrow Transplantation, 2017, 23(4):691-696

Scott SA, Dong WF, Ichinohasama R, Hirsch C, Sheridan D, Sanche SE, Geyer CR, Decoteau JF. 5-Aza-2’-deoxycytidine (decitabine) can relieve p21WAF1 repression in human acute myeloid leukemia by a mechanism involving release of histone deacetylase 1 (HDAC1) without requiring p21WAF1 promoter demethylation. Leukemia Research, 2006, 30(1):69-76

Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM. Effects of 5-Aza-2’-deoxycytidine (decitabine) on gene expression. Drug Metabolism Reviews, 2018, 50(2):193-207

Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S, Imai K, Kantarjian HM, Issa JP, Garcia-Manero G. Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood, 2003, 101(10):4131-4136

Shi H, Guo J, Duff DJ, Rahmatpanah F, Chitima-Matsiga R, Al-Kuhlani M, Taylor KH, Sjahputera O, Andreski M, Wooldridge JE, Caldwell CW. Discovery of novel epigenetic markers in non-Hodgkin’s lymphoma. Carcinogenesis, 2007, 28(1):60-70

Sorror ML, Gooley TA, Maclean KH, Hubbard J, Marcondes MA, Torok-Storb BJ, Tewari M. Pre-transplant expressions of MicroRNAs, comorbidities, and post-transplant mortality. Bone Marrow Transplantation, 2019, 54(7):973-979

Takam Kamga P, Dal Collo G, Midolo M, Adamo A, Delfino P, Mercuri A, Cesaro S, Mimiola E, Bonifacio M, Andreini A, Chilosi M, Krampera M. Inhibition of Notch signaling enhances chemosensitivity in B-cell precursor acute lymphoblastic leukemia. Cancer Research, 2019, 79(3):639-649

Tamm I, Wagner M, Schmelz K. Decitabine activates specific caspase downstream of p73 in myeloid leukemia. Ann Hematol 84 Suppl, 2005, 1: 47-53

Tang B, Cai Z, Wang Z, Lin D, He X, Li Q, Liang X, Huang K, Zhou X, Lin R, Xu N, Fan Z, Huang F, Sun J, Liu X, Liu Q, Zhou H. Allogeneic hematopoietic stem cell transplantation overcome the. Poor prognosis of patients with IKZFplus CD20-a very high-risk subtype in B-cell acute lymphoblastic leukemia. Bone Marrow Transplantation, 2022, 57(12):1751-1757

Taylor KH, Pena-Hernandez KE, Davis JW, Arthur GL, Duff DJ, Shi H, Rahmatpanah FB, Sjahputera O, Caldwell CW. Large-scale CpG methylation analysis identifies novel candidate genes and reveals methylation hotspots in acute lymphoblastic leukemia. Cancer Research, 2007, 67(6):2617-2625

Tosi M, Spinelli O, Leoncin M, Cavagna R, Pavoni C, Lussana F, Intermesoli T, Frison L, Perali G, Carobolante F, Viero P, Skert C, Ranbaldi A, Bassan R. MRD-Based therapeutic decisions in genetically define subsets of. Adolescents and young adult Philadelphia-Negative ALL. Cancers (Basel), 2021, 13(9):2108

Touzart A, Boissel N, Belhocine M, Smith C, Graux C, Latiri M, Lhermitte L, Mathieu EL, Huguet F, Lamant L, Ferrier P, Ifrah N, Macintyre E, Dombret H, Asnafi V, Spicuglia S. Low level CpG Island promoter methylation predicts a poor outcome in adult T-cell acute lymphoblastic leukemia. Haematologica, 2020, 105(6):1575-1581

van Otterdijk SD, Norden J, Dickinson AM, Pearce MS, Relton CL, Mathers JC, Strathdee G. Aberrations in DNA methylation are detectable during remission of acute lymphoblastic leukemia and predict patient outcome. Epigenomics, 2015, 7(1):35-45

van Outersterp I, Boer JM, van de Ven C, Reichert CEJ, Boeree A, Kruisinga B, de Groot-Kruseman HA, Escherich G, Sijs-Szabo A, Rijneveld AW, den Boer ML. Tyrosine Kinase inhibitor resistance in de Novo BCR::ABL1-positive BCP-ALL beyond. Kinase domain mutations. Blood Adv, 2024, 8(8):1835-1845

Wang CX, Wang X, Liu HB, Zhou ZH. Aberrant DNA methylation and epigenetic inactivation of hMSH2 decreases overall survival of acute lymphoblastic leukemia patients via modulating cell cycle and apoptosis. Asian Pacific Journal of Cancer Prevention, 2014, 15(1):355-362

Xiu M, Wang Y, Li B, Wang X, Xiao F, Chen S, Zhang L, Zhou B, Hua F. The role of Notch3 signaling in Cancer stemness and chemoresistance: Molecular mechanisms and targeting strategies. Front Mol Biosci, 2021, 14: 8694141

Yánez L, Bermúdez A, Richard C, Bureo E, Iriondo A. Successful induction therapy with decitabine in refractory childhood acute lymphoblastic leukemia. Leukemia, 2009, 23(7):1342-1343

Yang H, Thomas DA, Rytting ME, Zweidler-McKay PA, Brown DL, Kantarjian H, Garcia-Manero G. Phase I study of frequent low-dose administration of decitabine, alone or in combination with hypercvad, in relapsed or refractory acute lymphocytic leukemia (ALL). Journal of Clinical Oncology, 2007, 25: 18suppl7072

Yang H, Kadia T, Xiao L, Bueso-Ramos CE, Hoshino K, Thomas DA, O’Brien S, Jabbour E, Pierce S, Rosner GL, Kantarjian HM, Garcia-Manero G. Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia. Blood, 2009, 113(9):1892-1898

Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell, 2014, 26(4):577-590

Yao J, Zhang XB, Zhang XL, Fu WL. Methylation status of oestrogen receptor alpha-A: A predictor of prognosis in leukaemias. Bioscience Reports, 2010, 30(4):217-222

Yasuda T, Sanada M, Tsuzuki S, Hayakawa F. Oncogenic lesions and molecular subtypes in adults with B-cell acute lymphoblastic leukemia. Cancer Science, 2023, 114(1):8-15

Yoo KH, Won KY, Lim SJ, Park YK, Chang SG. Deficiency of MSH2 expression is associated with clear cell renal cell carcinoma. Oncol Lett, 2014, 8(5):2135-2139

Younesian S, Shahkarami S, Ghaffari P, Alizadeh S, Mehrasa R, Ghavamzadeh A, Ghaffari SH. DNA hypermethylation of tumor suppressor genes RASSF6 and RASSF10 as independent prognostic factors in adult acute lymphoblastic leukemia. Leukemia Research, 2017, 61: 33-38

Younesian S, Shahkarami S, Ghaffari P, Alizadeh S, Mehrasa R, Ghaffari SH. Residual methylation of tumor suppressor gene promoters, RASSF6 and RASSF10, as novel biomarkers for minimal residual disease detection in adult acute lymphoblastic leukemia. Annals of Hematology, 2019, 98(12):2719-2727

Zebley CC, Brown C, Mi T, Fan Y, Alli S, Boi S, Galletti G, Lugli E, Langfitt D, Metais JY, Lockey T, Meagher M, Triplett B, Talleur AC, Gottschalk S, Youngblood B. CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia. Cell Rep, 2021, 37(9):110079

Zhang Y, Hu CF, Chen J, Yan LX, Zeng YX, Shao JY. LATS2 is de-methylated and overexpressed in nasopharyngeal carcinoma and predicts poor prognosis. Bmc Cancer, 2010, 8: 10538

Zhang P, Weng WW, Chen P, Zhang Y, Ruan JF, Ba DD, Xu WQ, Tang YM. Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome. Int J Lab Hematol, 2019, 41(5):702-709

Zhao Z, Chen L, Dawlaty MM, Pan F, Weeks O, Zhou Y, Cao Z, Shi H, Wang J, Lin L, Chen S, Yuan W, Qin Z, Ni H, Nimer SD, Yang FC, Jaenisch R, Jin P, Xu M. Combined loss of Tet1 and Tet2 promotes B cell, but not myeloid malignancies, in mice. Cell Rep, 2015, 13(8):1692-1704

Zhao A, Zhou H, Yang J, Li M, Niu T. Epigenetic regulation in hematopoiesis and its. Implications in the targeted therapy of hematologic malignancies. Signal Transduct Target Ther, 2023, 8(1):71

Zhi, Y., Li, X., Li, J., Wu, Z., & Zhu, J. (2019). Decitabine combined with chemotherapy in treatment of relaosed/refractory acute lymphocytic leukemia: Report of one case and review of literature. J Leukemia & Lymphomas, 28. https://doi.org/10.3760/CMA.J.ISSN.1009-9921.2019.09.009

Funding

National Natural Science Foundation of China http://dx.doi.org/10.13039/501100001809(82470229); Shenzhen Clinical Research Center of Hematology(LCYSSQ20220823091401002); Sanming Project of Medicine in Shenzhen(SZSM202111004); Shenzhen Key Laboratory Foundation(ZDSYS20200811143757022); Medicine Plus Program of Shenzhen University(000003011601)