Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice

Biying Zhu, Wenbin Zhong, Xiuye Cao, Guoping Pan, Mengyang Xu, Jie Zheng, Huanzhao Chen, Xiaoqin Feng, Chengwei Luo, Chen Lu, Jie Xiao, Weize Lin, Chaofeng Lai, Mingchuan Li, Xin Du, Qing Yi, Daoguang Yan

Research output: Contribution to journalArticlepeer-review

Abstract

Leukemia stem cells (LSCs) propagate leukemia and are responsible for the high frequency of relapse of treated patients. The ability to target LSCs remains elusive, indicating a need to understand the underlying mechanism of LSC formation. Here, we report that miR-31-5p is reduced or undetectable in human LSCs compared to hematopoietic stem progenitor cells (HSPCs). Inhibition of miR-31-5p in HSPCs promotes the expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing factor 1α (HIF-1α)], to suppress HIF-1α signaling. Increased FIH resulted in a switch from glycolysis to oxidative phosphorylation (OXPHOS) as the predominant mode of energy metabolism and increased the abundance of the oncometabolite fumarate. Increased fumarate promoted the conversion of HSPCs to LSCs and initiated myeloid leukemia-like disease in NOD-Prkdcscid IL2rgtm1/Bcgen (B-NDG) mice. We further demonstrated that miR-31-5p inhibited long- and short-term hematopoietic stem cells with a high frequency of LSCs. In combination with the chemotherapeutic agent Ara-C (cytosine arabinoside), restoration of miR-31-5p using G7 poly (amidoamine) nanosized dendriplex encapsulating miR-31-5p eliminated LSCs and inhibited acute myeloid leukemia (AML) progression in patient-derived xenograft mouse models. These results demonstrated a mechanism of HSC malignant transformation through altered energy metabolism and provided a potential therapeutic strategy to treat patients with AML.

Original languageEnglish (US)
Article numbereabh2548
JournalScience translational medicine
Volume14
Issue number629
DOIs
StatePublished - Jan 26 2022

ASJC Scopus subject areas

  • Medicine(all)

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