Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells

# Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells *Published: 2026 May 1* bioRxiv. 2025 Jul 16:2025.07.16.664824. doi: 10.1101/2025.07.16.664824. The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression. DOI: 10.1016/j.cell.2026.04.014