Understanding a high-risk acute myeloid leukemia by analyzing the interactome of its major driver mutation.

Autor: Claudia Chiriches, Nathalie Nicolaisen, Maria Wieske, Heba Elhaddad, Ecmel Mehmetbeyoglu, Caroline Alvares, Dörte Becher, Paul Hole, Oliver Gerhard Ottmann, Martin Ruthardt
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: PLoS Genetics, Vol 18, Iss 10, p e1010463 (2022)
Druh dokumentu: article
ISSN: 1553-7390
1553-7404
DOI: 10.1371/journal.pgen.1010463
Popis: The WHO classifies t(6;9)-positive acute myeloid leukemia (AML) as a subgroup of high-risk AML because of its clinical and biological peculiarities, such as young age and therapy resistance. t(6;9) encodes the DEK/NUP214 fusion oncoprotein that targets only a small subpopulation of bone marrow progenitors for leukemic transformation. This distinguishes DEK/NUP214 from other fusion oncoproteins, such as PML/RARα, RUNX1/ETO, or MLL/AF9, which have a broad target population they block differentiation and increase stem cell capacity. A common theme among most leukemogenic fusion proteins is their aberrant localization compared to their wild-type counterparts. Although the actual consequences are widely unknown, it seems to contribute to leukemogenesis most likely by a sequester of interaction partners. Thus, we applied a global approach to studying the consequences of the aberrant localization of t(6;9)-DEK/NUP214 for its interactome. This study aimed to disclose the role of localization of DEK/NUP214 and the related sequester of proteins interacting with DEK/NUP214 for the determination of the biology of t(6;9)-AML. Here we show the complexity of the biological consequences of the expression of DEK/NUP214 by an in-depth bioinformatic analysis of the interactome of DEK/NUP214 and its biologically dead mutants. DEK/NUP214's interactome points to an essential role for aberrant RNA-regulation and aberrant regulation of apoptosis and leukocyte activation as a significant determinant of the phenotype of t(6;9)-AML. Taken together, we provide evidence that the interactome contributes to the aberrant biology of an oncoprotein, providing opportunities for developing novel targeted therapy approaches.
Databáze: Directory of Open Access Journals
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