Molecular leveraging of HOX-embedded non-coding RNAs in the progression of acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by impaired differentiation of myeloid cells leading to hematopoietic failure. Despite advances, the molecular mechanisms driving AML remain incompletely understood, limiting the identification and targeting of critical vulnerabilities in leukemic cells. Homeobox (HOX) genes, encoding transcription factors essential for myeloid and lymphoid differentiation, are distributed across four clusters: HOXA (chromosome 7), HOXB (chromosome 17), HOXC (chromosome 12), and HOXD (chromosome 2). In addition to protein-coding sequences, HOX clusters encode non-coding RNAs (ncRNAs), which are functional as transcripts and do not translate into proteins. This is the first study wherein we comprehensively reviewed the literature for HOX-embedded ncRNAs, encompassing long non-coding RNAs (lncRNAs), microRNAs, circular RNAs (circRNAs), and piwiRNAs with a role in AML. To date, there is no evidence of circular RNAs and piwi RNAs encoded from the HOX gene clusters. Our review focuses on how leukemic cells harness the regulatory mechanisms of HOX-cluster-derived ncRNAs, (predominantly HOXA and HOXB) to modulate expression of HOX transcription factors facilitating leukemogenesis. HOX ncRNAs either regulate genes on the same chromosome (e.g., lncRNA HOTTIP) or influence expression of genes on different chromosomes (e.g., HOTAIR, HOX10-AS, miR-196b, and miR-10a). We discuss how specific HOX ncRNA networks are leveraged by leukemic cells, presenting an opportunity to explore targeted therapies and address the molecular heterogeneity of AML. Additionally, the aberrant expression of HOX ncRNAs such as HOXB derived ncRNAs in NPM1 mutated AML suggests their potential utility as improved biomarkers and for prognostication of patients with specific molecular aberrations.