Asunto(s)
Proteínas de la Membrana/genética , Neoplasias/genética , Translocación Genética/genética , Tirosina Quinasa 3 Similar a fms/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 3/genética , Eosinofilia/genética , Reordenamiento Génico , Proteínas de la Matriz de Golgi , HumanosRESUMEN
Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Leucemia Mielomonocítica Crónica/patología , Monocitos/citología , Proteínas Proto-Oncogénicas c-ret/genética , Secuencia de Bases , Cartilla de ADN , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielomonocítica Crónica/genética , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Translocación GenéticaRESUMEN
Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.