Stem cell-enriched long non-coding RNA HOXA-AS4 contributes to the pathogenesis of MLL-rearranged AML

Introduction: Homeobox (HOX) genes play an essential role during embryogenesis and hematopoiesis. Their dysregulation is crucial for MLL-induced leukemogenesis. To date, the contribution of long non-coding RNAs (lncRNAs) located within the HOXA-cluster to the pathogenesis of AML remains unknown.

Results: Our microarray lncRNA expression atlas for the hematopoietic system, including 46 pediatric AML patient samples, revealed upregulation of HOXA-AS4 in hematopoietic stem and progenitor cells, (HSPCs) various MLL-cell lines and MLL-patient blasts. Expression was low to absent in differentiated blood cells and non-MLL cell lines. These findings were confirmed by qRT-PCR. Lentiviral overexpression of the lncRNA using a bidirectional lentiviral vector system inhibited granulocytic and monocytic differentiation of HSPCs and enhanced leukemic growth in primary MLL blasts and ML-2 cells.

Conclusion: We identified lncRNA HOXA4-AS as a potential onco-lncRNA in MLL-rearranged leukemia with potential homeostatic function in HSPCs. Mechanistically HOXA-AS4 mediates a differentiation block in HSPCs and contributes to the leukemic growth of leukemic blasts.