Abstract
Chromosomal translocations involving the nucleoporin NUP98 gene are recurrently identified in leukemia; yet, the cellular defects accompanying NUP98 fusion proteins are poorly characterized. NUP98 fusions cause changes in nuclear and nuclear envelope (NE) organization, in particular, in the nuclear lamina and the lamina associated polypeptide 2α (LAP2α), a regulator of the tumor suppressor retinoblastoma protein (RB). We demonstrate that, for NUP98-HOXA9 (NHA9), the best-studied NUP98 fusion protein, its effect(s) on nuclear architecture largely depend(s) on RB. Morphological alterations caused by the expression of NHA9 are largely diminished in the absence of RB, both in human cells expressing the human papillomavirus 16 E7 protein and in mouse embryonic fibroblasts lacking RB. We further show that NHA9 expression associates with distinct histone modification. Moreover, the pattern of trimethylation of histone H3 lysine-27 is affected by NHA9, again in an RB-dependent manner. Our results pinpoint to an unexpected interplay between NUP98 fusion proteins and RB, which may contribute to leukemogenesis.
Highlights
We described in detail an aberrant nuclear envelope phenotype caused by the expression of NUP98 fusion proteins in transfected human cell lines, in transduced mouse bone marrow cells, and in patient-derived samples [23]
We showed here that for NHA9, the appearance of these morphological alterations was largely diminished in the absence of retinoblastoma protein (RB), both in human cells expressing the human papillomavirus (HPV) 16 E7 protein and in triple knockout (TKO)
Our data suggested that the aberrant nuclear envelope (NE) phenotype correlated with changes in chromatin organization, in particular trimethylation of histone H3K27, in an RB-dependent manner
Summary
Chromosomal translocations affecting the NUP98 gene are recurrently identified in hematopoietic malignancies. These rearrangements result in fusion proteins involving the N terminus of NUP98 (N98) fused in frame to about 30 distinct partner proteins [1,2,3,4]. The fusion partners include various homeodomain (HD) transcription factors as well as other chromatin-binding proteins. N98 is an integral part of the nuclear pore complex (NPC), and it is roughly comprised of two domains: an N-terminal GLFG
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