The New England journal of medicine · 2009
Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Mullighan Charles G, Su Xiaoping, Zhang Jinghui, Radtke Ina, Phillips Letha A A, Miller Christopher B, Ma Jing, Liu Wei, Cheng Cheng, Schulman Brenda A, Harvey Richard C, Chen I-Ming, Clifford Robert J, Carroll William L, Reaman Gregory, Bowman W Paul, Devidas Meenakshi, Gerhard Daniela S, Yang Wenjian, Relling Mary V, Shurtleff Sheila A, Campana Dario, Borowitz Michael J, Pui Ching-Hon, Smith Malcolm, Hunger Stephen P, Willman Cheryl L, Downing James R, Children's Oncology Group
Аннотация
BACKGROUND: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.
METHODS: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.
RESULTS: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.
CONCLUSIONS: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.
METHODS: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.
RESULTS: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.
CONCLUSIONS: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.
Предметные рубрики MeSH
B-LymphocytesChildCohort StudiesDNA Mutational AnalysisDrug Resistance, NeoplasmGene DeletionGene ExpressionGene Expression ProfilingGenotypeHematopoietic Stem CellsHumansIkaros Transcription FactorMutation, MissensePAX5 Transcription FactorPrecursor B-Cell Lymphoblastic Leukemia-LymphomaPrognosisRecurrenceTrans-ActivatorsTreatment Outcome