Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.

慢性粒细胞白血病 (CML) 的疾病进展和复发是由治疗耐药的白血病干细胞 (LSC) 引起的，治愈依赖于它们的根除。已知骨髓 (BM) 中的微环境有助于 LSC 的维持和抵抗。尽管脾脏的白血病浸润是 CML 的标志，但尚不清楚脾细胞是否形成维持 LSC 的生态位。在这里，我们证明 LSC 优先在脾脏中积累并促进疾病进展。在 CML 患者和小鼠 CML 模型中，脾脏 LSC 位于接近红髓巨噬细胞 (RPM) 的红髓中。RPM 的药理学和遗传耗竭减少了 LSC 并降低了它们在脾脏中的细胞循环活动。基因表达分析显示脾脏白血病干细胞和祖细胞 (LSPCs) 中干性增加，骨髓谱系分化减少。这些结果表明，脾脏 RPM 形成了一个生态位，可将 CML LSC 维持在静止状态，从而导致疾病进展和对治疗的抵抗。