Decreased RNA-binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide.

Autor: Lin Z; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.; Department of Hematology, The Affiliated Hospital of Chengdu University, Chengdu, China., Zhang Y; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Liu X; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Luo H; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Li Q; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Gao Q; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Wang X; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Wen J; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.; Department of Hematology, Mian-Yang Central Hospital, Mianyang, China., Li L; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Feng Y; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Wang F; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Huang J; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Zhai X; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Zhang L; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Niu T; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China., Zheng Y; Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2024 Aug; Vol. 205 (2), pp. 594-606. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1111/bjh.19468
Abstrakt: 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. hnRNPU Low 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 Crbn I391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.
(© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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