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NUP98-BPTF promotes oncogenic transformation through PIM1 upregulation. | LitMetric

NUP98-BPTF promotes oncogenic transformation through PIM1 upregulation.

Cancer Med

Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Published: July 2024

AI Article Synopsis

  • NUP98 fusion proteins, like NUP98-BPTF (NB), are commonly linked to leukemia and poor outcomes, impacting gene regulation crucial for cancer development.
  • In experiments, the NB fusion was introduced into mouse and human cells, revealing that it encourages cancer cell transformation by increasing the expression of the proto-oncogene Pim1 and activating specific signaling pathways.
  • The study highlights the significance of NB in promoting cell survival and transformation, pinpointing Pim1 as a vital target for potential leukemia therapies.

Article Abstract

Introduction: Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown.

Materials And Methods: To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells.

Results: NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD).

Conclusion: We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212001PMC
http://dx.doi.org/10.1002/cam4.7445DOI Listing

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