The long non-coding RNA FAM30A regulates the Musashi2-RUNX1 axis and is required for LSC function in AML cells

High expression of the long non-coding RNA (lncRNA) FAM30A has been previously associated with leukemic stem cell (LSC) activity and poor prognosis in both adult and paediatric acute myeloid leukaemia (AML) patients, yet it has not been functionally studied. This study provides the first cellular characterization of FAM30A focussing on an internal tandemly organised region, referred to as FAM30A repeats. FAM30A levels correlated with canonical AML LSC signatures and FAM30A depletion decreased cell viability as well as increased sensitivity to chemotherapeutics. It also inhibited colony formation, promoted granulocytic differentiation and abrogated leukemic engraftment in murine bone marrow in vivo. Overexpression of FAM30A repeats in this setting enhanced stemness, proliferation, chemoresistance, and engraftment thus highlighting the biological relevance of this region for LSC biology. On the molecular level, FAM30A repeats interact with the pro-LSC regulator Musashi-2 (MSI2), positively influencing expression of its targets including RUNX1 isoforms. We herein uncover that this FAM30A-MSI2-RUNX1 regulatory loop is of potential relevance for LSC maintenance in AML. These findings provide valuable insights into FAM30As cellular role and highlight its targeting potential for eliminating LSCs and improving treatment outcomes in AML patients.