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Recurrent Rearrangement of the Ewing’s Sarcoma Gene, EWSR1, or Its Homologue, TAF15, with the Transcription Factor CIZ/NMP4 in Acute Leukemia¹

Center for Human Genetics, University of Leuven, Campus Gasthuisberg O&N06, B-3000 Leuven, Belgium [A. M., H. J., A. C., R. S., A. H., P. M.]; Flanders Interuniversity Institute for Biotechnology (VIB), Belgium [A. M., H. J., A. C., R. S., P. M.]; Department of Hematology, University of Perugia, Policlinico Monteluce, I-06100 Perugia, Italy [R. L. S., C. M.]; Hematology, University Victor Segalen Bordeaux, Pessac 33 604, Bordeaux, France [C. B-N.]; Hospital de Sant Pau, 08025 Barcelona, Spain [A. A.]; and University "La Sapienzia," 00161 Rome, Italy [R. F.]

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.

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