Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development

Abstract Essential thrombocythemia (ET) includes the JAK2 ‐, CALR ‐, and MPL ‐mutated subtypes, and a triple‐negative (TN) ET subtype, which lacks these canonical drivers. How specific driver mutations affect hematopoietic stem cell (HSC) heterogeneity and their relation to ET pathogenesis remain unclear. Here, by using single‐cell RNA sequencing (scRNA‐seq) combined with driver mutation detection across ET patients, it is found that MPL ‐mutated HSCs exhibited aberrant metabolism, CALR ‐mutated HSCs displayed active cell cycling, while JAK2 ^V617F ‐mutated HSCs demonstrated enhanced megakaryocyte (Mk) priming capacity and interferon (IFN) response. An HSC subset is identified in TN ET that transcriptionally resembled driver‐mutated HSCs, exhibiting enhanced megakaryocytic priming and proliferative activity. Notably, the frequency of a CXCR4 ⁺ HSC subset is reduced across the ET spectrum. Loss of CXCR4 ⁺ HSCs skewed lineage differentiation of HSCs toward the myeloid lineage, whereas restoring this subset delayed the onset of ET. Altogether, this study reveals both the shared and distinct molecular features of mutant HSCs in ET and provides novel insights into the pathogenesis and potential therapeutic strategies of ET.