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

Autor: Michael D. Radmacher, Sebastian Schwind, Kati Maharry, Susan P. Whitman, Klaus H. Metzeler, Joseph O. Moore, Richard A. Larson, Deedra Nicolet, Meir Wetzler, Andrew J. Carroll, Heiko Becker, Krzysztof Mrózek, Jihane Khalife, Michael A. Caligiuri, Jessica Kohlschmidt, Maria R. Baer, Jonathan E. Kolitz, Bayard L. Powell, Guido Marcucci, Jason H. Mendler, Thomas H. Carter, Clara D. Bloomfield
Rok vydání: 2012
Předmět:
Male
Oncology
Cancer Research
Time Factors
DNA Mutational Analysis
Kaplan-Meier Estimate
Gene mutation
medicine.disease_cause
Polymerase Chain Reaction
Risk Factors
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
CEBPA
Oligonucleotide Array Sequence Analysis
Aged
80 and over
Mutation
Age Factors
Middle Aged
Gene Expression Regulation
Neoplastic
Leukemia
Myeloid
Acute
Leukemia
Phenotype
Treatment Outcome
Core Binding Factor Alpha 2 Subunit
Cytogenetic Analysis
Disease Progression
Female
Nucleophosmin
medicine.drug
Adult
NPM1
medicine.medical_specialty
Adolescent
Risk Assessment
Disease-Free Survival
Young Adult
Internal medicine
Original Reports
medicine
Humans
Genetic Predisposition to Disease
Aged
Proportional Hazards Models
business.industry
Gene Expression Profiling
Cancer
medicine.disease
United States
Gene expression profiling
MicroRNAs
Logistic Models
Multivariate Analysis
Immunology
Cytarabine
business
Zdroj: Journal of Clinical Oncology. 30:3109-3118
ISSN: 1527-7755
0732-183X
Popis: 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. 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. 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. 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.
Databáze: OpenAIRE
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