title: A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a 'core enriched' (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CE(high)) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CE(high) patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CE(low) patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CE(high) status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CE(high) patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: K
authors.initials: K
authors.lastname: Maharry
authors.forename: J
authors.initials: J
authors.lastname: Kohlschmidt
authors.forename: S
authors.initials: S
authors.lastname: Volinia
authors.forename: K
authors.initials: K
authors.lastname: Mrózek
authors.forename: H
authors.initials: H
authors.lastname: Becker
authors.forename: D
authors.initials: D
authors.lastname: Nicolet
authors.forename: S P
authors.initials: SP
authors.lastname: Whitman
authors.forename: J H
authors.initials: JH
authors.lastname: Mendler
authors.forename: S
authors.initials: S
authors.lastname: Schwind
authors.forename: A-K
authors.initials: AK
authors.lastname: Eisfeld
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Wu
authors.forename: B L
authors.initials: BL
authors.lastname: Powell
authors.forename: T H
authors.initials: TH
authors.lastname: Carter
authors.forename: M
authors.initials: M
authors.lastname: Wetzler
authors.forename: J E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: M R
authors.initials: MR
authors.lastname: Baer
authors.forename: A J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012074:Remission Induction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D059467:Transcriptome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs