Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Neoplasias Primarias Secundarias/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Subunidad alfa 2 del Factor de Unión al Sitio Principal/análisis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Exones/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/análisis , Proteína 1 Compañera de Translocación de RUNX1/análisis , Adulto JovenRESUMEN
We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.
Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Proteínas de Fusión Oncogénica/análisis , Adolescente , Adulto , Anciano , Subunidad alfa 2 del Factor de Unión al Sitio Principal/análisis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Proteína 1 Compañera de Translocación de RUNX1/análisis , Proteína 1 Compañera de Translocación de RUNX1/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Translocación Genética , Adulto JovenRESUMEN
We describe a unique presentation of acute myeloid leukaemia (AML) with myeloid sarcoma (MS), manifested as proptosis with multiple cranial nerve palsies in a 9-year-old boy. MRI of the brain revealed multiple enhancing lesions and bilateral mastoiditis, in addition to sagittal sinus thrombosis. Peripheral blood smear demonstrated blasts showing Auer rods. Bone marrow examination confirmed the diagnosis of AML. PCR was positive for RUNX1-RUNX1T1. Neurological deficits improved with induction chemotherapy for AML. Extramedullary MS can present simultaneously with or antedate AML. Common genetic aberrations include t(8;21) and inv(16). Therapy is akin to AML. An effect of MS on survival outcomes is variable.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/análisis , Enfermedades de los Nervios Craneales/genética , Exoftalmia/genética , Leucemia Mieloide Aguda/complicaciones , Proteína 1 Compañera de Translocación de RUNX1/análisis , Niño , Humanos , Leucemia Mieloide Aguda/genética , MasculinoRESUMEN
Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34(+) cord blood cells in long-term culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models.
