RESUMEN
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.