title: Expression and prognostic impact of lncRNAs in acute myeloid leukemia.
abstract: Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; carlo.croce@osumc.edu ramiro.garzon@osumc.edu clara.bloomfield@osumc.edu.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, FE 44121, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Papaioannou
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN 55905;
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN 55905;
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Donna
authors.initials: D
authors.lastname: Bucci
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201;
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.affiliation: Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242;
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.affiliation: The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157;
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: North Shore Cancer Institute, Lake Success, NY 11042;
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Duke University and Durham VA Medical Centers, Durham, NC 27701; and.
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: James S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Dana-Farber Cancer Institute, Harvard University, Boston, MA 02215.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; carlo.croce@osumc.edu ramiro.garzon@osumc.edu clara.bloomfield@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; carlo.croce@osumc.edu ramiro.garzon@osumc.edu clara.bloomfield@osumc.edu.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D016022:Case-Control Studies; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D017423:Sequence Analysis, RNA; D015996:Survival Rate
chemical_list: C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; D000090243:Nucleophosmin
keywords: acute myeloid leukemia; lncRNAs; outcome