RESUMEN
Rearrangements in the distal region of the short arm of chromosome 1 are recurrent aberrations in a broad spectrum of human neoplasias. However, neither the location of the breakpoints (BP) on 1p36 nor the candidate genes have been fully determined. We have characterized, by fluorescence in situ hybridization (FISH), the BP in 26 patients with hematological neoplasias and 1p36 rearrangements in the G-banding karyotype. FISH allowed a better characterization of all samples analyzed. Nine cases (35%) showed reciprocal translocations, 15 (58%) unbalanced rearrangements, and two (7%) deletions. We describe two new recurrent aberrations. In 18 of the 26 cases analyzed the BP were located in band 1p36, which is 25.5 Mb long. In 14 of these 18 cases (78%) and without distinction between myeloid and lymphoid neoplasias, the BP clustered in a 2.5 Mb region located between 1p36.32 and the telomere. Interestingly, this region is contained in the 10.5 Mb cluster on 1p36.22-1pter defined in cases with 1p36 deletion syndrome. The 2.5 Mb region, located on 1p36.32-1pter, has a higher frequency of occurrence of tandem repeats and segmental duplications larger than 1 kb, when compared with the 25.5 Mb of the complete 1p36 band. This could explain its proneness for involvement in chromosomal rearrangements in hematological neoplasias.
Asunto(s)
Aberraciones Cromosómicas , Rotura Cromosómica , Deleción Cromosómica , Cromosomas Humanos Par 1 , Neoplasias Hematológicas/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Síndrome , Translocación GenéticaRESUMEN
We describe a new PDGFRB fusion associated with a t(5;14)(q33;q24) in a patient with a longstanding chronic myeloproliferative disorder with eosinophilia. After confirmation of PDGFRB involvement and definition of the chromosome 14 breakpoint by fluorescence in situ hybridization, candidate partner genes were selected on the basis of the presence of predicted oligomerization domains believed to be an essential feature of tyrosine kinase fusion proteins. We demonstrate that the t(5;14) fuses PDGFRB to NIN, a gene encoding a centrosomal protein with CEP110-like function. After treatment with imatinib, the patient achieved hematological and cytogenetical remission, but NIN-PDGFRB mRNA remained detectable by reverse transcription-PCR.
Asunto(s)
Antineoplásicos/uso terapéutico , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Secuencia de Bases , Benzamidas , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 5/genética , Reordenamiento Génico , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Masculino , Datos de Secuencia Molecular , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación GenéticaRESUMEN
ETV6/TEL is the first transcription factor identified that is specifically required for hematopoiesis within the bone marrow. This gene has been found to have multiple fusion partners of which 16 have been cloned. Fluorescence in situ hybridization (FISH) analysis in a patient with myelodysplastic syndrome (MDS) revealed a t(1;12)(p36;p13) involving ETV6, with the breakpoint in this gene between exon 2 and exon 3. We report here the cloning of a novel ETV6 partner located on 1p36.1, involved in the t(1;12). 3' RACE-PCR from RNA identified a novel sequence fused to exon 2 of ETV6. Database searches localized this sequence in a bacterial artificial chromosome (BAC) mapped to 1p36 by fingerprint analysis. This result was confirmed by FISH using this BAC as probe. 5' and 3' RACE experiments with primers from this novel sequence were carried out on RNA from a healthy donor and identified a novel full-length mRNA, which we named MDS2 (myelodysplastic syndrome 2). RT-PCR experiments were performed on a panel of human cDNAs to analyze the expression pattern of this gene and they revealed four splicing variants. RT-PCR analysis showed that ETV6-MDS2, but not the reciprocal MDS2-ETV6 fusion transcript, was expressed in the bone marrow of the patient. The product of the ETV6-MDS2 fusion transcript predicts a short ETV6 protein containing the first 54 amino acids of ETV6 plus four novel amino acids, lacking both the PTN and the DNA-binding domains. Possible mechanisms to account for the development of MDS in this patient are discussed.
