[Paper Review] Hematopoietic cancers and Nup98 fusions: determining common mechanisms of malignancy

Juliana S. Capitanio, Richard W. Wozniak|arXiv (Cornell University)|Jan 1, 2014

Genomics and Chromatin Dynamics55 references1 citations

TL;DR

The paper investigates how Nup98 fusions act as aberrant transcriptional regulators in hematopoietic stem cells, driving leukemogenesis through dysregulation of genes involved in embryonic development, immune function, and chromatin organization. By analyzing published microarray data, it identifies shared transcription factor networks that are co-opted by multiple fusions, revealing a common molecular mechanism underlying Nup98-related malignancies.

ABSTRACT

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.

Motivation & Objective

• To determine the common molecular mechanisms by which Nup98 fusions contribute to hematopoietic malignancies.
• To investigate whether Nup98 fusions function as rogue transcriptional regulators by altering gene expression programs.
• To identify shared downstream target genes and regulatory networks across diverse Nup98 fusion variants.
• To explore the functional interconnectivity of transcription factors bound to deregulated gene promoters in Nup98 fusion-expressing cells.
• To link chromatin-binding capacity of Nup98 fusions to the activation of oncogenic transcriptional programs in leukemia stem cells.

Proposed method

• Analysis of publicly available microarray gene expression data from hematopoietic stem cells expressing Nup98 fusions.
• Identification of differentially expressed genes across multiple Nup98 fusion models to detect common transcriptional signatures.
• Functional enrichment analysis of deregulated genes to uncover overrepresented biological processes.
• Prediction of transcription factor binding sites in the regulatory regions of shared target genes using computational motif analysis.
• Construction of protein-protein interaction and transcriptional regulatory networks among candidate transcription factors.
• Integration of gene expression, transcription factor binding, and network topology to infer core regulatory circuits.

Experimental results

Research questions

• RQ1 Do Nup98 fusions consistently alter the expression of a common set of target genes across different fusion variants?
• RQ2 Which biological processes are most significantly dysregulated by Nup98 fusion-driven transcriptional changes?
• RQ3 Are there shared transcription factor binding motifs in the regulatory regions of deregulated genes, suggesting coordinated regulation?
• RQ4 How interconnected are the candidate transcription factors in the regulatory network, and do they form a core oncogenic module?
• RQ5 To what extent does the chromatin-binding capacity of Nup98 fusions correlate with the activation of developmental and hematopoietic transcriptional programs?

Key findings

• Over 75% of Nup98 fusions interact with chromatin, indicating a widespread capacity to directly influence transcriptional regulation.
• Commonly deregulated genes are enriched in biological processes related to embryonic development, immune system formation, and chromatin organization.
• Deregulated genes share conserved transcription factor binding sites in their regulatory regions, suggesting coordinated transcriptional control.
• The candidate transcription factors bound to these regulatory regions form a highly interconnected network through protein-protein interactions and transcriptional cross-regulation.
• These transcription factors play critical roles in cell cycle regulation, hematopoiesis, apoptosis, and chromatin modification, linking them to leukemogenesis.
• The convergence of multiple Nup98 fusions on a shared set of transcription factors and target genes reveals a common oncogenic transcriptional circuit.