Hematopoietic cancers and Nup98 fusions: determining common mechanisms of malignancy

TL;DR

This study investigates how Nup98 gene fusions in hematopoietic stem cells act as rogue transcriptional regulators, affecting gene expression and biological processes related to leukemia development.

Contribution

It provides a comprehensive analysis of gene expression changes caused by Nup98 fusions and identifies common regulatory mechanisms involved in hematopoietic malignancies.

Findings

Nup98 fusions influence genes involved in development, immune formation, and chromatin organization.

Deregulated genes share transcription factor binding sites and regulatory networks.

Similar gene expression patterns are observed across different Nup98 fusion types.

Abstract

Chromosomal aberrations are very frequent in leukemias and several recurring mutations capable of malignant transformation have been described. These mutations usually occur in hematopoietic stem cells (HSC), transforming them into leukemia stem cells. NUP98 gene translocations are an example of such chromosomal aberrations; these translocations produce a fusion protein containing the N-terminal portion of Nup98 and the C-terminal of a fusion partner. Over 75% of Nup98 fusions can interact with chromatin, and lead to changes in gene expression. Therefore, I hypothesize that nup98 fusions act as rogue transcriptional regulators in the cell. Collecting previously published gene expression data (microarray) from HSCs expressing Nup98 fusions, we can generate data to corroborate this hypothesis. Several different fusions affect the expression of similar genes; these are involved in a few biological processes in the cell: embryonic development, immune system formation and chromatin organization. Deregulated genes also present similar transcription factor binding sites in their regulatory regions. These putative regulatory transcription factors are highly interconnected through protein-protein interactions and transcriptional regulation among themselves, and they have important roles in cell cycle regulation, embryonic development, hematopoiesis, apoptosis and chromatin modification.