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

Chiriches, Claudia ORCID: https://orcid.org/0000-0003-3758-1892, Nicolaisen, Nathalie, Wieske, Maria, Elhaddad, Heba, Mehmetbeyoglu, Ecmel, Alvares, Caroline ORCID: https://orcid.org/0000-0003-4391-9802, Becher, Dörte, Hole, Paul, Ottmann, Oliver Gerhard ORCID: https://orcid.org/0000-0001-9559-1330 and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2022. Understanding a high-risk acute myeloid leukemia by analyzing the interactome of its major driver mutation. PLoS Genetics 18 (10) , e1010463. 10.1371/journal.pgen.1010463

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Public Library of Science
ISSN:	1553-7390
Date of First Compliant Deposit:	8 November 2022
Date of Acceptance:	4 October 2022
Last Modified:	11 Oct 2023 22:07
URI:	https://orca.cardiff.ac.uk/id/eprint/154042

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