MALNC: A new mutant NPM1/IDH2R140 and PML-RARA-associated lncRNA with impact on AML cell proliferation, maturation and drug response

As the non-coding genome remains poorly characterized in acute myeloid leukemia (AML), we aimed to identify and functionally characterize novel long non-coding RNAs (lncRNAs) relevant to AML biology and treatment. We first identified lncRNAs overexpressed in AML blasts and discovered a novel lncRNA, which we named myeloid and AML-associated intergenic long non-coding RNA (MALNC). MALNC is overexpressed in AML, particularly in cases with the PML-RARA fusion or IDH2R140/NPM1 co-mutations, and is associated with a distinct gene expression profile. Functional studies showed that MALNC knockout impairs AML cell proliferation and colony formation, enhances ATRA-induced differentiation, and sensitizes cells to arsenic trioxide. Transcriptomic analysis revealed that MALNC loss alters the expression of retinoic acid pathway genes, and chromatin binding studies showed that MALNC binds to genes related to the retinoic acid and Rho GTPase pathways. In conclusion, we have identified MALNC as a novel lncRNA that promotes leukemic cell proliferation, counteracts ATRA-induced differentiation, and modulates drug sensitivity in AML. Overall design: CRISPR-Cas9 editing was used to generate several MALNC-knockout (KO) in NB4 cell lines by deleting various TSSs. In KOA, Ex1.1 and Ex1.2 were deleted, in KOB, Ex1.0 was deleted. Three NB4 KOA, three NB4 KOB and three NB4 WT clones were selected for RNA-seq analysis at basal level. Additionally, one NB4 KOB clone and one NB4 WT clone were treated in three biological replicates with ATRA (1µM) for 72h and subject to RNA-seq.