Functional analysis of the NUP98-CCDC28A fusion protein

Abstract

The nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation. To gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice. Our in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions. Our results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.