Key Points• The lncRNA HOXA10-AS is highly expressed in KMT2A-rearranged AMLs and exerts its oncogenic effects by inducing NF-kB target genes.• Knockdown of HOXA10-AS reduces the leukemic growth of KMT2A-rearranged AML blasts in vivo.HOX genes are highly conserved, and their precisely controlled expression is crucial for normal hematopoiesis. Accordingly, deregulation of HOX genes can cause leukemia.However, despite of intensive research on the coding HOX genes, the role of the numerous long noncoding RNAs (lncRNAs) within the HOX clusters during hematopoiesis and their contribution to leukemogenesis are incompletely understood. Here, we show that the lncRNA HOXA10-AS, located antisense to HOXA10 and mir-196b in the HOXA cluster, is highly expressed in hematopoietic stem cells (HSCs) as well as in KMT2A-rearranged and NPM1 mutated acute myeloid leukemias (AMLs). Using short hairpin RNA-and locked nucleic acid-conjugated chimeric antisense oligonucleotide (LNA-GapmeR)-mediated HOXA10-AS-knockdown and CRISPR/Cas9-mediated excision in vitro, we demonstrate that HOXA10-AS acts as an oncogene in KMT2A-rearranged AML. Moreover, HOXA10-AS knockdown severely impairs the leukemic growth of KMT2A-rearranged patient-derived xenografts in vivo, while high HOXA10-AS expression can serve as a marker of poor prognosis in AML patients. Lentiviral expression of HOXA10-AS blocks normal monocytic differentiation of human CD34 1 hematopoietic stem and progenitor cells. Mechanistically, we show that HOXA10-AS localizes in the cytoplasm and acts in trans to induce NF-kB target genes. In total, our data imply that the normally HSC-specific HOXA10-AS is an oncogenic lncRNA in KMT2A-r AML. Thus, it may also represent a potential therapeutic target in KMT2A-rearranged AML.

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Children with Down syndrome (DS) are predisposed to developing megakaryoblastic leukemia (ML-DS) and often experience severe toxicities from chemotherapy, highlighting the need for targeted therapies with beneficial risk profiles. The genomic landscape of ML-DS is characterized by a combination of mutations in signaling pathway genes and epigenetic modifiers, while aberrant lysine specific demethylase 1 (LSD1) and JAK-STAT activation have both been implicated in leukemogenesis. Here, we demonstrate that combined LSD1 and JAK1/2 inhibition exerts synergistic anti-leukemic effects specifically in ML-DS, both in vitro and in patient derived xenografts in vivo. The JAK1/2 inhibitor ruxolitinib enhanced the LSD1 inhibitor-induced differentiation, proliferation arrest and apoptosis in patient-derived leukemic blasts. At the transcriptional level, the combination synergistically repressed gene expression signatures essential for cell division. We further observed an immunogenic gene expression pattern in the form of increased cytokine signaling, which - by sensitizing ML-DS blasts to the JAK-STAT signaling blockade induced by ruxolitinib - could explain the increased susceptibility of ML-DS blasts to combination therapy. Taken together, we establish combined LSD1 and JAK-STAT inhibition as an efficacious therapeutic regimen specifically designed to target important steps in ML-DS leukemogenesis, paving the way for targeted therapies in this entity.