RESUMO
We report a NUMA1-PDGFRB fusion in a myeloproliferative neoplasm with eosinophilia in a 61-year old man, with response to imatinib mesylate therapy. A t(5;11) chromosome translocation involving bands 5q32 and 11q13.4 was identified by metaphase chromosome analysis, and rearrangement of the platelet-derived growth factor receptor beta (PDGFRB) gene on 5q32 was demonstrated by FISH using a PDGFRB break-apart probe set. Bacterial artificial chromosome (BAC) FISH mapping of the PDGFRB fusion partner gene narrowed the breakpoint at 11q13.4 to a 150 kb genomic region containing three genes, including NUMA1. Mate pair sequencing analysis demonstrated NUMA1-PDGFRB fusion. The fusion protein includes coiled-coil domains of nuclear mitotic apparatus protein 1 (NuMA1, involved in protein homodimerization and heteroassociation) and tyrosine kinase domains of PDGFRB. Diverse rearrangements involving the PDGFRB gene have been identified in myeloid and lymphoid neoplasms with eosinophilia, but rearrangement of the nuclear mitotic apparatus protein 1 (NUMA1) gene has previously been reported in a human malignancy in only one instance, a NUMA1-RARA fusion caused by a t(11;17) translocation in a patient with acute promyelocytic leukemia. The NUMA1-PDGFRB fusion is the second instance of rearrangement of NUMA1, encoding an element of the mitotic apparatus, in human cancer.
Assuntos
Antígenos Nucleares/genética , Eosinofilia/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Proteínas Associadas à Matriz Nuclear/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas de Ciclo Celular , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Eosinofilia/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Resultado do TratamentoRESUMO
Sickle cell anemia is one of the most common autosomal recessive diseases in the world. Patients with sickle cell anemia have variable penetrance and it is hard to predict the risk and timing of complications. It is characterized by a point mutation in the beta-globin gene (GAG --> GTG) and the production of hemoglobin S. The latter leads to decreased deformability of the red blood cells (RBCs) that adhere to endothelia cells culminating in vascular occlusion and its sequelae of tissue ischemia and organ damage. Moreover, sickled RBCs undergo intravascular hemolysis and accelerated erythropoesis. The hallmarks of this disease are shortened RBC survival and vaso-occlusive crises. For the past ten years, the pathophysiology of this disease has been better elucidated and has led to significant improvements in the standard of care. Vaso-occlusion is now understood to be a complex event that involves abnormal interactions between RBCs, leukocytes, endothelial cells and the coagulation pathways. The field of translational research in sickle cell anemia has expanded greatly and has led to new clinical trials with new therapeutic agents and strategies. In this paper, we review the drugs that are now being investigated in the treatment of sickle cell anemia.
