title: Transcriptome Profiling of Pediatric Core Binding Factor AML.
abstract: The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t(8;21) (N = 17), Inv(16) (N = 14), and normal karyotype (NK, N = 33) were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t(8;21) and 474 genes in Inv(16) were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes (175/198; binomial test p-value < 10(-30)) are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events (ASEs) differentially expressed across subtypes, with 337 t(8;21)-specific and 407 Inv(16)-specific ASEs detected, the majority of which were acetylated proteins (p = 1.5 x 10(-51) and p = 1.8 x 10(-54) for the two subsets). In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients. Clustering of differentially expressed genes indicated that the homeobox (HOX) gene family, including two transcription factors (MEIS1 and NKX2-3) were down-regulated in CBF compared to NK samples. This finding supports existing data that the dysregulation of HOX genes play a central role in biology CBF-AML hematopoiesis. These data provide comprehensive transcriptome profiling of CBF-AML and delineate genes and pathways that are differentially expressed, providing insights into the shared biology as well as differences in the two CBF subsets.
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Cu
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yan
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ostronoff
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Komatsoulis
authors.affiliation: Hudson Alpha Institute for Biotechnology, Huntsville, AL, United States of America.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America.
authors.forename: Daoud
authors.initials: D
authors.lastname: Meerzaman
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000107:Acetylation; D017398:Alternative Splicing; D001665:Binding Sites; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D025341:Principal Component Analysis; D011485:Protein Binding; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C534957:NKX2-3 protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors