RESUMEN
We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.
Asunto(s)
Antraciclinas/administración & dosificación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Adolescente , Niño , Preescolar , Quimioterapia de Consolidación/métodos , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Humanos , Quimioterapia de Inducción/métodos , Lactante , Japón , Leucemia Promielocítica Aguda/complicaciones , Quimioterapia de Mantención/métodos , Masculino , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Tretinoina/administración & dosificaciónRESUMEN
OTT/RBM15-BSAC/MAL/MKL1/MRTF-A was identified as a fusion transcript generated by t(1;22)(p13;q13) in acute megakaryoblastic leukemia. Previous studies have shown that BSAC (basic, SAP, and coiled-coil domain) activates the promoters containing CArG boxes via interaction with serum response factor, and OTT (one twenty-two) negatively regulates the development of megakaryocytes and myeloid cells. However, the mechanism by which OTT-BSAC promotes leukemia is largely unknown. Here we show that OTT-BSAC, but not BSAC or OTT strongly activates several promoters containing a transcription factor Yin Yang 1-binding sequence. In addition, although BSAC predominantly localizes in the cytoplasm and its nuclear translocation is considered to be regulated by the Rho-actin signaling pathway, OTT-BSAC exclusively localizes in the nucleus. Moreover, OTT interacts with histone deacetylase 3, but this interaction is abolished in OTT-BSAC. Collectively, these functional and spatial changes of OTT and BSAC caused by the fusion might perturb their functions, culminating in the development of acute megakaryoblastic leukemia.
Asunto(s)
Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Leucemia Megacarioblástica Aguda/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Unión al ARN/metabolismo , Elementos de Respuesta , Transcripción Genética , Transporte Activo de Núcleo Celular/genética , Línea Celular Tumoral , Núcleo Celular/genética , Proteínas de Unión al ADN/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Leucemia Megacarioblástica Aguda/genética , Megacariocitos/metabolismo , Proteínas de Fusión Oncogénica/genética , Estructura Terciaria de Proteína/genética , Proteínas de Unión al ARN/genética , Elementos de Respuesta/genética , Transactivadores , Transcripción Genética/genética , Regulación hacia Arriba/genética , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
More than 40 genes have been reported as translocation partners of the mixed lineage leukemia gene (MLL) in hematologic malignancies. AF17 was identified earlier than most other MLL translocation partners. On the other hand, there is only 1 report of an MLL-AF17 fusion transcript in acute myeloid leukemia (AML). Here we describe a 40-year-old man with a diagnosis of AML involving t(11;17)(q23;q21). We identified a chromosomal breakpoint for t(11;17)(q23;q21) at MLL intron 6 and AF17 intron 8. Although the previously reported form of the MLL-AF17 fusion transcript was not detected by reverse transcriptase-polymerase chain reaction (PCR) analysis, a novel form of an MLL-AF17 fusion transcript joining MLL exon 6 to AF17 exon 9 was detected by complementary DNA panhandle PCR. The fact that 2 forms of MLL-AF17 retain the leucine zipper domain of AF17 suggests that the dimerization domain of AF17 is critical for leukemogenesis by the MLL-AF17 fusion gene.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Proteínas de Unión al ADN/genética , Leucemia Monocítica Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Adulto , Transformación Celular Neoplásica/genética , Rotura Cromosómica , N-Metiltransferasa de Histona-Lisina , Humanos , Leucina Zippers , Masculino , Proteínas de Fusión Oncogénica/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación GenéticaRESUMEN
We analysed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. MYO1F consists of at least 28 exons and was predicted to encode a 1098-amino-acid with an N-terminal head domain containing both ATP-binding and actin-binding sequences, a neck domain with a single IQ motif, and a tail with TH1, TH2 and SH3 domains. Northern blot analysis of RNAs prepared from multiple tissues showed that the expression of approximately 4-kb transcripts appeared constant in most tissues examined. However, MYO1F was expressed in only three of 22 leukemic cell lines. The MLL-MYO1F fusion protein contains almost the entire MYO1F, however, C-terminal MYO1F has neither the transactivation domain nor the dimerization domain found in various MLL fusion partners. Further analysis of this novel type of MLL fusion protein would provide new insights into leukemogenesis. MYO1F is the fourth partner gene of MLL on 19p13. At the cytogenetic level, it may be difficult to distinguish MLL-ENL, MLL-ELL, MLL-EEN and MLL-MYO1F fusions created by t(11;19)(q23;p13), and it is likely that cases of t(11;19) lacking a known fusion gene may result in this gene fusion.
Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia Monocítica Aguda/genética , Miosina Tipo I/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Translocación Genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular Tumoral , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 7 , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-LinfoideRESUMEN
There are a limited number of reports of acute myeloid leukemia (AML) with t(10;11)(q22;q23). We showed that the MLL gene on 11q23 was fused to the LCX (leukemia-associated protein with a CXXC domain) gene on 10q22 in a de novoadult AML-M2 with trilineage dysplasia having t(10;11)(q22;q23). LCX consisted of at least 12 exons and was predicted to encode a 2136-amino-acid protein with an estimated molecular mass of 235.3 kDa. The LCX protein had a zinc-binding CXXC domain that MLL also contains within a methyltransferase domain, three nuclear localization signals, an alpha-helical coiled-coil region, and two homologous regions to CG2083 proteins of Drosophila melanogaster. We found approximately 12-, 9.5-, and 7.5-kb transcripts of LCX. Expression of the 7.5-kb transcript was detected in fetal heart, lung, and brain, and in adult skeletal muscle, thymus, and ovary. Expression of the 9.5-kb transcript was detected in fetal lung and brain and in adult ovary. Expression of the 12-kb transcript was detected in fetal heart and brain and in adult thymus and ovary. LCX was expressed in 8 of 22 leukemic cell lines, but not in EBV-induced normal B-cell lines. The MLL-LCX fusion protein lacked a CXXC domain of LCX, but retained an alpha-helical coiled-coil region at the COOH terminus, similar to MLL-SEPTING, MLL-CDCREL1, MLL-AF1p/Eps15, and MLL-AF6, which suggests that these fusion proteins are involved in the pathogenesis of 11q23-associated leukemia through similar mechanisms.
Asunto(s)
Cromosomas Humanos Par 10 , Cromosomas Humanos Par 11 , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proto-Oncogenes , Factores de Transcripción , Translocación Genética , Anciano , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Rotura Cromosómica , Clonación Molecular , ADN Complementario/genética , ADN de Neoplasias/genética , Drosophila melanogaster/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Oxigenasas de Función Mixta , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas , Homología de Secuencia de AminoácidoRESUMEN
t(X;11) is a recurrent translocation in pediatric acute myeloid leukemia (AML). We showed that the MLL gene on 11q23 was fused to the SEPTIN6 gene on Xq24, a human homologue to mouse Septin6, in three de novo infant AML with complex chromosomal abnormalities involving 11q23 and Xq22-24. SEPTIN6 consisted of at least 12 exons and was predicted to encode at least two types of proteins by alternative splicing. Expression of approximately 2.3-, 3.1-, and 4.6-kb SEPTIN6 transcripts was simultaneously detected in fetal lung, liver, and brain, in all of the adult tissues except brain, and in acute lymphoblastic leukemia and AML cell lines. However, the expression of an approximately 2.7-kb transcript was detected alone in fetal heart and adult brain. The SEPTIN6 protein is homologous to septin family members including CDCREL1 and AF17q25/MSF, which generate fusion products with MLL. The MLL-SEPTIN6 fusion proteins contain almost the entire septin protein, similar to MLL-CDCREL1 and MLL-AF17q25/MSF. Notably, all three of the patients were diagnosed with M1 or M2. Combined present results and literatures suggest that AML with the MLL-SEPTIN6 fusion gene is a subset of infant AML, which differentiate into the myeloid lineage, although AML with other MLL fusion genes is capable of differentiating into the myelomonocytic or monocytic lineage.