title: RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.
abstract: Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marcos R H
authors.initials: MR
authors.lastname: Estécio
authors.forename: Sirisha
authors.initials: S
authors.lastname: Maddipoti
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Courtney D
authors.initials: CD
authors.lastname: DiNardo
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wei
authors.forename: Kimie
authors.initials: K
authors.lastname: Kondo
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Fang
authors.forename: William
authors.initials: W
authors.lastname: Stevenson
authors.forename: Kun-Sang
authors.initials: KS
authors.lastname: Chang
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Pierce
authors.forename: Zachary
authors.initials: Z
authors.lastname: Bohannan
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D007446:Chromosome Inversion; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D000077209:Decitabine; D001374:Azacitidine
keywords: DNA methylation; RUNX3; acute myeloid leukaemia; gene expression; inv(16)(p13.1q22)