Myelodysplastic neoplasms (MDS) are characterized by clonal evolution starting from the compartment of hematopoietic stem and progenitors cells (HSPCs), leading in some cases to leukemic transformation. We hypothesized that deciphering the diversity of the HSPCs compartment may allow for the early detection of an emergent sub-clone that drives disease progression. Deep analysis of HSPCs repartition by multiparametric flow cytometry revealed a strong disorder of the hematopoietic branching system in most patients at diagnosis with different phenotypic signatures closely related to specific MDS features. In two independent cohorts of 131 and 584 MDS, the HSPCs heterogeneity quantified through entropy calculation was decreased in 47% and 46% of cases, reflecting a more advanced state of the disease with deeper cytopenias, higher IPSS-R risk and accumulation of somatic mutations. We demonstrated that patients with lower-risk MDS and low CD34 + CD38+HSPCs entropy had an adverse outcome and that this parameter is as an independent predictive biomarker for progression free survival, leukemia free survival and overall survival. Analysis of HSPCs repartition at diagnosis represents therefore a very powerful tool to identify lower-risk MDS patients with a worse outcome and valuable for clinical decision-making, which could be fully integrated in the MDS diagnostic workflow.

骨髓增生异常肿瘤 (MDS) 的特点是从造血干细胞和祖细胞 (HSPC) 区室开始克隆进化，在某些情况下导致白血病转化。我们假设破译 HSPC 区室的多样性可能有助于及早发现驱动疾病进展的新兴亚克隆。通过多参数流式细胞术对 HSPC 重新分配的深入分析显示，大多数诊断时患者的造血分支系统存在严重紊乱，具有与特定 MDS 特征密切相关的不同表型特征。在 131 例和 584 例 MDS 的两个独立队列中，通过熵计算量化的 HSPC 异质性在 47% 和 46% 的病例中下降，反映了疾病的更晚期状态，血细胞减少更深、IPSS-R 风险更高和体细胞突变积累。我们证明，低风险 MDS 和低 CD34+CD38+HSPCs 熵的患者具有不良结局，并且该参数可作为无进展生存期、无白血病生存期和总生存期的独立预测生物标志物。因此，诊断时 HSPC 重新分配的分析是一种非常强大的工具，可以识别结果较差的低风险 MDS 患者，并且对临床决策有价值，可以完全集成到 MDS 诊断工作流程中。