Akademik Veri Yönetim Sistemi
PLOS GENETICS, cilt.18, sa.10, 2022 (SCI-Expanded)
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/RAR alpha, 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. Author summary The frequency of acute myeloid leukemia (AML), the most common acute leukemia in adults, increases with age while its outcome worsens. Risk stratification subdivides AML patients into good, intermediate, and poor risk groups concerning their overall survival (OS). The presence of tumor-specific genetic modifications and mutated proteins they encode influences the OS of a patient. Unfortunately, their role in OS and therapy response is not well understood. Here, we started with the commonalities most of these disease-defining modifications share. One is their aberrant localization within the tumor cells, accompanied by the changed localization of their interactor proteins. By studying all proteins interacting with one AML-defining mutated protein, we better understood the signaling pathways it disturbs. We found that the mutated protein studied, apart from programmed cell death and activation of white blood cells, strongly influences RNA-regulation through its interactors. RNA is transcribed from the genetic information encoded in the DNA and is responsible by many different mechanisms for correctly translating this information into proteins. Our findings define both new biomarkers and novel targets of molecular therapy. We expect to contribute to overcoming therapy resistance and thereby improve the overall survival of AML patients, particularly in the poor risk group.