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PIM3-mediated phosphorylation stabilizes myeloid leukemia factor 2 to promote metastasis in osteosarcoma

Cuiling Zeng1, Xin Wang1, Jinkun Zhong1

  • 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

The Journal of Clinical Investigation
|October 15, 2025
PubMed

Insights

Myeloid leukemia factor 2 (MLF2) drives osteosarcoma lung metastasis by disrupting the BiP-IRE1α interaction. Targeting the PIM3/MLF2 pathway offers a potential therapeutic strategy for osteosarcoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Osteosarcoma is the most common primary bone cancer.
  • Lung metastasis is a frequent and severe complication of osteosarcoma.
  • Limited therapeutic targets exist for osteosarcoma, especially for metastatic disease.

Purpose of the Study:

  • To identify novel molecular drivers of osteosarcoma lung metastasis.
  • To elucidate the mechanism by which MLF2 promotes metastasis.
  • To explore potential therapeutic targets for osteosarcoma metastasis.

Main Methods:

  • In vivo CRISPR activation screening in osteosarcoma models.
  • Interactome analysis focusing on STUB1.
  • Investigation of the IRE1α/XBP1-S-MMP9 signaling pathway.
  • Analysis of protein modifications (ubiquitination, phosphorylation) and degradation.

Main Results:

  • Myeloid leukemia factor 2 (MLF2) was identified as a promoter of osteosarcoma metastasis.
  • MLF2 disrupts the BiP-IRE1α interaction, activating the IRE1α/XBP1-S-MMP9 axis.
  • STUB1 targets MLF2 for degradation, while PIM3-mediated phosphorylation stabilizes MLF2 via USP21.
  • The PIM3/MLF2 axis is a critical regulator of osteosarcoma lung metastasis.

Conclusions:

  • MLF2 plays a key role in osteosarcoma lung metastasis through the IRE1α/XBP1-S-MMP9 pathway.
  • The interplay between PIM3, MLF2, STUB1, and USP21 regulates MLF2 stability and function.
  • PIM3 inhibition represents a promising therapeutic strategy for osteosarcoma with lung metastasis.
Keywords:
CancerCell biologyOncologyProtein kinasesUbiquitin-proteosome system

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