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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.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2012 Sep 01; Vol. 30 (25), pp. 3109-18. Date of Electronic Publication: 2012 Jul 02. - Publication Year :
- 2012
-
Abstract
- Purpose: 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.<br />Patients and 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.<br />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.<br />Conclusion: 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.
- Subjects :
- Adolescent
Adult
Age Factors
Aged
Aged, 80 and over
DNA Mutational Analysis
Disease Progression
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute mortality
Leukemia, Myeloid, Acute pathology
Logistic Models
Male
Middle Aged
Multivariate Analysis
Nucleophosmin
Oligonucleotide Array Sequence Analysis
Phenotype
Polymerase Chain Reaction
Proportional Hazards Models
Risk Assessment
Risk Factors
Time Factors
Treatment Outcome
United States
Young Adult
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Core Binding Factor Alpha 2 Subunit genetics
Cytogenetic Analysis
Gene Expression Profiling methods
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute genetics
MicroRNAs metabolism
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 30
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 22753902
- Full Text :
- https://doi.org/10.1200/JCO.2011.40.6652