GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301055/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301055GEOGSEfalseTranscriptomic profiling of human CD34⁺/CD45RA-/CD90+ HSCs folowing lncRNA CRISPR/Cas9 editing and cytosine base editing [bulk_RNAseq]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 find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we have named 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.2026/05/01GSE301055GSM9074380GSM9074381GSM9074379GSM9074375GSM9074376GSM9074377GSM9074378GSM9074382GSM9074383GSM9074372GSM9074373GSM907437430173301055Homo sapiens