RESUMO
We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.
Assuntos
Regulação Leucêmica da Expressão Gênica , Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Animais , Células da Medula Óssea/patologia , Células da Medula Óssea/fisiologia , Células COS , Chlorocebus aethiops , Perfilação da Expressão Gênica , Células HeLa , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Células NIH 3T3 , Transplante de NeoplasiasRESUMO
Tyrosine kinases activated by mutation or translocation are involved in the chronic phase of myeloproliferative disorders. Complementary or alternative events are not so well characterized. We report here a case of t(8;13) generating a ZNF198-FGFR1 fusion kinase gene on the derivative chromosome 13. ZNF198-FGFR1 mRNA, but not FGFR1-ZNF198, was detected by polymerase chain reaction amplification. By using fluorescence in situ hybridization with BAC clones, we mapped a deletion of about 2 megabases on the derivative chromosome 8, including the reciprocal FGFR1-ZNF198 fusion gene and the surrounding genes from 8p11 and 13q12. Potential tumor suppressor genes affected by the deletion by loss (IFT88, CRYL1, TACC1) or break (LATS2) may participate in the malignant process.
Assuntos
Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Deleção de Genes , Genes Supressores de Tumor , Transtornos Mieloproliferativos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Translocação Genética , Adolescente , Adulto , Coloração Cromossômica , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 8 , Feminino , Fusão Gênica , Humanos , Cariotipagem , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição , Transcrição GênicaRESUMO
Fusions of the TET-proteins (TLS/FUS, EWSR1, and TAF15/RBP56) to different transcription factors are involved in various malignancies including Ewing's sarcoma, primitive neuroectodermal tumors, and acute myeloid leukemia. These are thought to arise through transcriptional deregulation, with the transcription factor defining the tumor phenotype. We show that, as result of a t(12;17)(p13;q11) or its variant t(12;22)(p13;q12), the transcription factor gene CIZ/NMP4 is recurrently involved in acute leukemia through fusion with either EWSR1 or TAF15. The fusions possess transforming properties in NIH3T3 cells but do not affect the expression of CIZ target genes, suggesting a contribution to oncogenesis that is independent of the transactivating properties of the fusion protein. These results also extend the involvement of TET-protein fusions to acute lymphoblastic leukemia and suggest a role for CIZ/NMP4 in lymphoid and myeloid development.