Asunto(s)
Evolución Clonal/genética , Reordenamiento Génico , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Biomarcadores de Tumor , Biopsia , Médula Ósea/metabolismo , Aberraciones Cromosómicas , Progresión de la Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación/métodos , Persona de Mediana Edad , Neoplasia Residual/diagnósticoAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antígenos CD19/inmunología , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Inmunoterapia/efectos adversos , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Femenino , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , PronósticoRESUMEN
Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P = .004) and inv(16) subtype (P = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P = .14). The repertoire of KIT, FLT3, and NRAS/KRAS variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P < 10-4), whereas the presence of a single signaling clone did not (P = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.
Asunto(s)
Evolución Clonal/genética , Factores de Unión al Sitio Principal/metabolismo , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Mutación , Transducción de Señal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Niño , Preescolar , Aberraciones Cromosómicas , Femenino , Regulación Leucémica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.
