Acute Myeloid Leukemia (AML) is one of the most aggressive hematologic malignancies, characterized by clonal expansion of undifferentiated myeloid progenitors. It predominantly affects the elderly population, and current treatment options remain largely limited to conventional chemotherapy, with a five‑year survival rate of only about 30%. The emergence of chemotherapy‑resistant leukemia‑initiating cells (LICs) frequently leads to disease relapse, underscoring the urgent need for novel therapeutic targets that can effectively eliminate LICs without compromising normal hematopoiesis.

In a study published in Science Translational Medicine on May 6, a research team led by Dr. WANG Lan from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, together with collaborators from multiple institutions, uncovered a critical role of the RNA‑binding protein RBPMS in driving AML progression and proposed a small‑molecule inhibitor targeting the RBPMS-FOXO1 axis.

The researchers found that RBPMS is upregulated in AML patients, and its high expression correlates with poor overall survival. Functional studies showed that RBPMS sustains the self‑renewal of leukemia stem cells and promotes leukemogenesis. Importantly, genetic ablation of Rbpms in mouse models had little effect on normal hematopoietic stem cell self‑renewal, multi‑lineage differentiation, or long‑term reconstitution capacity, suggesting that RBPMS represents an effective and safe therapeutic target.

Mechanistically, RBPMS recognizes and binds specific motifs on FOXO1 mRNA through its RRM domain. It recruits the m⁶A reader IGF2BP3 to enhance FOXO1 mRNA stability in an m⁶A‑dependent manner, leading to upregulation of FOXO1 protein. Moreover, RBPMS facilitates FOXO1‑mediated transcriptional activation of key glycolytic enzymes, thereby boosting glycolysis in AML cells.

Based on the structural information of the RBPMS RRM domain, the team designed and screened a small‑molecule inhibitor. Using multiple models including AML mouse models, patient‑derived AML cells, and patient‑derived xenograft (PDX) mouse models, the researchers validated the therapeutic efficacy of the RBPMS inhibitor against AML, which holds significant implications and translational prospects for the clinical treatment of AML.

In summary, this study revealed the molecular mechanism by which RBPMS drives the progression of acute myeloid leukemia, established a regulatory link between RNA post-transcriptional regulation and metabolic reprogramming in AML, and provided a potential new strategy for precision therapy of AML.

Molecular Mechanisms and Targeted Strategies for RBPMS Regulation of Acute Myeloid Leukemia Onset and Progression.
(Image by Dr. WANG Lan's group)

Paper link: https://www.science.org/doi/10.1126/scitranslmed.adv8951

Scientific Contact:
Dr. WANG Lan
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: lwang@sinh.ac.cn

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn