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

This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration. To interrogate the mechanistic role of DEK in B-cell lymphoma, we generated a DEK knockout cell line model, which demonstrated DEK depletion caused reduced proliferation and altered expression of key cell cycle and apoptosis-related proteins, including Bcl-2, Bcl-xL, and p53. Notably, DEK depleted cells showed increased sensitivity to apoptosis-inducing agents, including venetoclax and staurosporine, which underscores the therapeutic potential of targeting DEK in B-cell lymphomas. Overall, our study contributes to a better understanding of DEK’s role as an oncoprotein in B-cell lymphomas, highlighting its potential as both a promising therapeutic target and a novel biomarker for aggressive LGBCL. Further research elucidating the molecular mechanisms underlying DEK-mediated tumorigenesis could pave the way for improved treatment strategies and better clinical outcomes for patients with B-cell lymphoma.

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DEK-rRNA interactions regulate ribosome biogenesis and stress response

Xu,

Chen,

Prell

et al. 2024

Preprint

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DNA/chromatin-based functions of the DEK oncogene, a unique nucleic acid-interacting factor in metazoans, have been widely investigated, yet its role in cellular RNA biology is under-studied. Herein we employed CLIP-seq alongside mutational, biochemical, and cellular approaches to gain deeper insights into the cellular DEK-RNA interplay. We confirm interaction of DEK with coding RNA, yet also report association with ribosomal RNA (rRNA) and thereby establishing a robust link between DEK and ribosome biology. Indeed, cells lacking DEK showed marked deficits in cytoplasmic ribosome quality and function. This phenotype was exclusively rescued by C-terminal DEK, harboring two RNA interaction domains, but not by an rRNA-binding deficient mutant. Mechanistically, we uncovered pleiotropic involvement of DEK in RNA polymerase I-mediated rRNA transcription and processing pathways. More specifically, we found direct interaction of DEK with RNA polymerase III-transcribed 5S rRNA and identified DEK as a regulator of the Impaired Ribosome Biogenesis Checkpoint (IRBC). Within this ribosomal stress pathway, DEK depletion results in free 5S RNP, triggering stabilization of p53 via inhibition of MDM2. In summary, our multilayer analysis revealed DEK as a potent cellular RNA binding protein and provides first evidence of DEK as a regulator of ribosome biogenesis and stress response via the 5S RNP-MDM2-p53 axis.

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

Cited by 4 publications

References 49 publications

The impact of the chromatin binding DEK protein in hematopoiesis and acute myeloid leukemia

The impact of the chromatin binding DEK protein in hematopoiesis and acute myeloid leukemia

DEK regulates B-cell proliferative capacity and is associated with aggressive disease in low-grade B-cell lymphomas

DEK-rRNA interactions regulate ribosome biogenesis and stress response

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