Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

Guillen, Nathalie; Wieske, Maria; Otto, Albrecht; Aa, Mian; Rokicki, Michal Jaroslaw; Carrault, Guy; Alvares, Caroline; Hole, Paul S.; Held, Hannelore; Ottmann, Oliver G.; Becher, Dörte; Wilson, Marieangela C.; Heesom, KJ; Ruthardt, Martin; Chiriches, Claudia

doi:10.1101/464958

Cited by 2 publications

(1 citation statement)

References 63 publications

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“…Interestingly, a particular kinase inhibitor drug based treatment (sorafenib) for AML has been shown [51] to block SRC kinase-mediated STAT3 phosphorylation. The STAT5 activation, on the other hand, is regulated by an interplay between SRC family kinases and the mammalian target of rapamycin (MTOR) via AKT/MTOR signaling pathway [52]. These terms are closely related in the estimated network through caspase-9 (CASP9) and integrin beta-3 (ITGB3).…”

Section: Plos Computational Biologymentioning

confidence: 99%

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

2021

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A wide variety of 1) parametric regression models and 2) co-expression networks have been developed for finding gene-by-gene interactions underlying complex traits from expression data. While both methodological schemes have their own well-known benefits, little is known about their synergistic potential. Our study introduces their methodological fusion that cross-exploits the strengths of individual approaches via a built-in information-sharing mechanism. This fusion is theoretically based on certain trait-conditioned dependency patterns between two genes depending on their role in the underlying parametric model. Resulting trait-specific co-expression network estimation method 1) serves to enhance the interpretation of biological networks in a parametric sense, and 2) exploits the underlying parametric model itself in the estimation process. To also account for the substantial amount of intrinsic noise and collinearities, often entailed by expression data, a tailored co-expression measure is introduced along with this framework to alleviate related computational problems. A remarkable advance over the reference methods in simulated scenarios substantiate the method’s high-efficiency. As proof-of-concept, this synergistic approach is successfully applied in survival analysis, with acute myeloid leukemia data, further highlighting the framework’s versatility and broad practical relevance.

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Section: Plos Computational Biologymentioning

confidence: 99%

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

2021

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Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes

Jühlen

Bousbata

et al. 2020

Cells

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The interaction of oncogenes with cellular proteins is a major determinant of cellular transformation. The NUP98-HOXA9 and SET-NUP214 chimeras result from recurrent chromosomal translocations in acute leukemia. Functionally, the two fusion proteins inhibit nuclear export and interact with epigenetic regulators. The full interactome of NUP98-HOXA9 and SET-NUP214 is currently unknown. We used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. Other cellular processes appear to be distinctively affected by the particular fusion protein. NUP98-HOXA9 likely perturbs Wnt, MAPK, and estrogen receptor (ER) signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, mitochondrial proteins and metabolic regulators are significantly overrepresented in the SET-NUP214 proximal interactome. Our study provides new clues on the mechanistic actions of nucleoporin fusion proteins and might be of particular relevance in the search for new druggable targets for the treatment of nucleoporin-related leukemia.

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Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

Cited by 2 publications

References 63 publications

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

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