MiR-551b-3p as a Therapeutic Vulnerability in Adverse-Risk Acute Myeloid Leukemia
Acute myeloid leukemia (AML) arising from hematopoietic stem cells (HSCs) or multipotent 1progenitors (MPPs) has been associated with increased therapy resistance compared to AML 2originating from more differentiated progenitors. In normal hematopoiesis, miR-551b-3p is 3predominantly expressed in HSC and MPP compartments, while its expression is lower in more 4mature cells. In AML, higher miR-551b-3p levels have been linked to adverse clinical 5outcomes. 6In this study, we observed that miR-551b-3p expression is relatively low or absent in favorable- 7risk, CD34-negative AML, whereas higher expression is more frequently detected in CD34- 8positive AML. Elevated miR-551b-3p levels were associated with molecular features linked to 9high-risk disease, including EVI1 overexpression and mutations in RUNX1 or TP53. Moreover, 10miR-551b-3p expression was higher in leukemic stem cells (LSCs) with an HSC/MPP-like 11phenotype. 12Functional analyses suggest that miR-551b-3p contributes to proliferation and maintenance of 13primary AML cells and is associated with reduced sensitivity to doxorubicin. Conversely, 14inhibition of miR-551b-3p reduced proliferation, promoted differentiation, and decreased the 15frequency of LSCs and leukemic progenitors in CD34-positive AML samples, while having 16limited effects on normal HSCs. Mechanistically, FOXO3A is identified as a potential target of 17miR-551b-3p. 18Together, these findings indicate that miR-551b-3p is associated with immature LSC 19phenotypes and adverse-risk AML features, and suggest that modulation of miR-551b-3p may 20represent a potential strategy to target leukemic stem and progenitor cells.