title: RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures.
abstract: OBJECTIVE
  To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures.
  
  
  METHODS
  Younger (< 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays.
  
  
  RESULTS
  RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P < .001) and inversely associated with NPM1 (P < .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P < .001 in older), overall survival (P = .003 in younger; P < .001 in older), and event-free survival (P < .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation-associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223.
  
  
  CONCLUSIONS
  RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches.
authors: The Ohio State University, Comprehensive Cancer Center, 1216 James Cancer Hospital, 300 West 10th Ave, Columbus, OH 43210, USA.
authors: Jason H
authors: JH
authors: Mendler
authors: Kati
authors: K
authors: Maharry
authors: Michael D
authors: MD
authors: Radmacher
authors: Krzysztof
authors: K
authors: Mrózek
authors: Heiko
authors: H
authors: Becker
authors: Klaus H
authors: KH
authors: Metzeler
authors: Sebastian
authors: S
authors: Schwind
authors: Susan P
authors: SP
authors: Whitman
authors: Jihane
authors: J
authors: Khalife
authors: Jessica
authors: J
authors: Kohlschmidt
authors: Deedra
authors: D
authors: Nicolet
authors: Bayard L
authors: BL
authors: Powell
authors: Thomas H
authors: TH
authors: Carter
authors: Meir
authors: M
authors: Wetzler
authors: Joseph O
authors: JO
authors: Moore
authors: Jonathan E
authors: JE
authors: Kolitz
authors: Maria R
authors: MR
authors: Baer
authors: Andrew J
authors: AJ
authors: Carroll
authors: Richard A
authors: RA
authors: Larson
authors: Michael A
authors: MA
authors: Caligiuri
authors: Guido
authors: G
authors: Marcucci
authors: Clara D
authors: CD
authors: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016015:Logistic Models; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; C000716967:NPM1 protein, human; C493728:RUNX1 protein, human; D000090243:Nucleophosmin