title: Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies.
abstract: Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 gene--member of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders.
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Puda
authors.forename: Jelena D
authors.initials: JD
authors.lastname: Milosevic
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Thorsten
authors.initials: T
authors.lastname: Klampfl
authors.forename: Ashot S
authors.initials: AS
authors.lastname: Harutyunyan
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.forename: Michael
authors.initials: M
authors.lastname: Steurer
authors.forename: Natasa
authors.initials: N
authors.lastname: Tosic
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D000208:Acute Disease; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics / Q000648:ultrastructure*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C119809:AEBP2 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C547777:JARID2 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497703:PHF19 protein, human; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2