NUP98‐BPTF promotes oncogenic transformation through PIM1 upregulation

Author:

Noura Mina1ORCID,Tomita Sakura1,Yasuda Takahiko2,Tsuzuki Shinobu3,Kiyoi Hitoshi4,Hayakawa Fumihiko1ORCID

Affiliation:

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

2. Clinical Research Center, National Hospital Organization Nagoya Medical Center Nagoya Japan

3. Department of Biochemistry Aichi Medical University School of Medicine Nagakute Japan

4. Department of Hematology and Oncology Nagoya University Graduate School of Medicine Nagoya Japan

Abstract

AbstractIntroductionNucleoporin 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 MethodsTo 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.ResultsNB 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).ConclusionWe 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.

Funder

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Publisher

Wiley

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