title: Hypomethylation of TET2 Target Genes Identifies a Curable Subset of Acute Myeloid Leukemia.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification.
  
  
  METHODS
  We used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy. Data were analyzed with hierarchical clustering, Cox proportional hazards regression, and Kaplan-Meier analyses. All statistical tests were two-sided.
  
  
  RESULTS
  In the test cohort, hierarchical clustering analysis identified low levels of tet2-DMC methylation in 31 of 94 (33%) cases, and these had markedly longer overall survival (median survival 72+ vs 14 months, P = .002). Similar results were seen in the validation cohort. tet2-DMC-low status was shown to be an independent predictor of overall survival (hazard ratio = 0.29, P = .0002). In The Cancer Genome Atlas (TCGA) dataset where DNA methylation was analyzed by a different platform, tet2-DMC-low methylation was also associated with improved outcome (median survival = 55 vs 15 months, P = .0003) and was a better predictor of survival than mutations in TET2, IDH1, or IDH2, individually or combined.
  
  
  CONCLUSIONS
  Low levels of tet2-DMC methylation define a subgroup of AML that is highly curable and cannot be identified solely by genetic and cytogenetic analyses.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Yamazaki
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Taby
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Noel J M
authors.initials: NJ
authors.lastname: Raynal
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Pierce
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bueso-Ramos
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX. jpissa@temple.edu.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000328:Adult; D000368:Aged; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013447:Sulfites
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D013447:Sulfites; D049308:Dioxygenases; C541081:TET2 protein, human; C042345:hydrogen sulfite