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

• Published in: PLoS genetics 2022-10, Vol.18 (10), p.e1010463-e1010463
• Main Authors: Chiriches, Claudia, Nicolaisen, Nathalie, Wieske, Maria, Elhaddad, Heba, Mehmetbeyoglu, Ecmel, Alvares, Caroline, Becher, Dörte, Hole, Paul, Ottmann, Oliver Gerhard, Ruthardt, Martin
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Amino acids; Apoptosis; Bone marrow; Bone Marrow - metabolism; Cell activation; Cell culture; Cell differentiation; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Gene expression; Gene mutations; Health aspects; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemogenesis; Localization; Medical prognosis; Methods; Molecular targeted therapy; Mutation; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Osteoprogenitor cells; Peptides; Phenotypes; Physiology; Poly-ADP-Ribose Binding Proteins - genetics; Progenitor cells; Proteins; Proteomics; Runx1 protein; Stem cells
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1010463

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.