title: Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles.
abstract: Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
authors.affiliation: Division of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Loudin
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: H-C Eastwood
authors.initials: HC
authors.lastname: Leung
authors.forename: S
authors.initials: S
authors.lastname: Gurusiddappa
authors.forename: J
authors.initials: J
authors.lastname: Meyer
authors.forename: G
authors.initials: G
authors.lastname: Condos
authors.forename: D
authors.initials: D
authors.lastname: Morrison
authors.forename: A
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: M
authors.initials: M
authors.lastname: Devidas
authors.forename: N A
authors.initials: NA
authors.lastname: Heerema
authors.forename: A J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: S E
authors.initials: SE
authors.lastname: Plon
authors.forename: S P
authors.initials: SP
authors.lastname: Hunger
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.forename: A
authors.initials: A
authors.lastname: Pession
authors.forename: D
authors.initials: D
authors.lastname: Bhojwani
authors.forename: W L
authors.initials: WL
authors.lastname: Carroll
authors.forename: K R
authors.initials: KR
authors.lastname: Rabin
mesh_terms: D001483:Base Sequence; D019175:DNA Methylation; D017931:DNA Primers; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006657:Histones / Q000235:genetics*; D006801:Humans; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D006657:Histones