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Decreased RNA-binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to
Zhimei Lin1,2, Yue Zhang1, Xiang Liu1
1Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.
Insights
Heterogeneous nuclear ribonucleoprotein U (hnRNPU) regulates lenalidomide (LEN) sensitivity in multiple myeloma (MM) by controlling mRNA translation. Lower hnRNPU levels enhance MM cell sensitivity to LEN, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Multiple myeloma (MM) is an incurable plasma cell malignancy.
- Lenalidomide (LEN) is a key treatment, but resistance is a clinical challenge.
- Mechanisms of LEN resistance require further elucidation.
Purpose of the Study:
- To investigate the role of heterogeneous nuclear ribonucleoprotein U (hnRNPU) in MM resistance to LEN.
- To elucidate the molecular mechanism by which hnRNPU influences LEN sensitivity.
Main Methods:
- RNA pulldown and electrophoretic mobility shift assays to identify hnRNPU-mRNA interactions.
- Sucrose gradient assays to assess mRNA translation regulation.
- In vivo studies using a Crbn-humanized MM mouse model.
Main Results:
- hnRNPU binds to the 3'-untranslated regions of CRBN and IKZF1 mRNA.
- hnRNPU represses the translation of CRBN and IKZF1 mRNA.
- Reduced hnRNPU levels in MM cells correlate with increased sensitivity to LEN.
- In vivo models confirm hnRNPU's role in MM response to LEN.
Conclusions:
- hnRNPU acts as a negative regulator of LEN sensitivity in MM by inhibiting CRBN and IKZF1 mRNA translation.
- Targeting hnRNPU-mediated translation repression may overcome LEN resistance in MM.
- This study reveals a novel mechanism influencing therapeutic response in multiple myeloma.
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