The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility. Open Access

• The lncRNA ELDR inhibits the leukemic potential of AML with MLL-r and enhances the therapeutic effect of ATRA and LSD1inhibitors

• The lncRNA ELDR exerts its anti-leukemic effect by inhibiting DNA replication and by reducing chromatin accessibility at centromeres.

Acute myeloid leukemia (AML) with rearrangement of the mixed lineage leukemia gene express MLL-AF9 fusion protein, a transcription factor that impairs differentiation and drives expansion of leukemic cells. We report here that the zinc finger protein GFI1 together with the histone methyltransferase LSD1 occupies the promoter and regulates expression of the lncRNA ELDR in the MLL-r AML cell line THP-1. Forced ELDR overexpression enhanced the growth inhibition of an LSD1i/ATRA combination treatment and reduced the capacity of these cells to generate leukemia in xenografts, leading to a longer leukemia-free survival. We found that ELDR binds the clamp protein PCNA and the MCM5 helicases causing defects of DNA replication fork progression. Moreover, AML cells overexpressing ELDR showed reduced chromatin accessibility and transcription at α-satellite repeats in centromeres. In addition, ELDR RNA was detected close to MLL-AF9 at centromeres suggesting that it impedes leukemic progression preferentially of MLL-r AML by interfering with both DNA replication and centromeric transcription. Our findings reveal novel functions of the lncRNA ELDR in DNA replication and centromere biology when expressed at high levels in AML cells with MLL rearrangements. These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be utilized as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.