Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA.
Department of Hematology and Oncology, Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
Cell Stem Cell. 2019 May 2;24(5):769-784.e6. doi: 10.1016/j.stem.2019.02.018. Epub 2019 Mar 21.
Chronic myeloid leukemia (CML) originates in a hematopoietic stem cell (HSC) transformed by the breakpoint cluster region (BCR)-abelson (ABL) oncogene and is effectively treated with tyrosine kinase inhibitors (TKIs). TKIs do not eliminate disease-propagating leukemic stem cells (LSCs), suggesting a deeper understanding of niche-dependent regulation of CML LSCs is required to eradicate disease. Cxcl12 is expressed in bone marrow niches and controls HSC maintenance, and here, we show that targeted deletion of Cxcl12 from mesenchymal stromal cells (MSCs) reduces normal HSC numbers but promotes LSC expansion by increasing self-renewing cell divisions, possibly through enhanced Ezh2 activity. In contrast, endothelial cell-specific Cxcl12 deletion decreases LSC proliferation, suggesting niche-specific effects. During CML development, abnormal clusters of colocalized MSCs and LSCs form but disappear upon Cxcl12 deletion. Moreover, MSC-specific deletion of Cxcl12 increases LSC elimination by TKI treatment. These findings highlight a critical role of niche-specific effects of Cxcl12 expression in maintaining quiescence of TKI-resistant LSC populations.
慢性髓性白血病 (CML) 起源于造血干细胞 (HSC)，其被断裂点簇区 (BCR)-abelson (ABL) 癌基因转化，并可通过酪氨酸激酶抑制剂 (TKI) 有效治疗。TKI 不能消除传播疾病的白血病干细胞 (LSCs)，这表明需要更深入地了解龛依赖性调节 CML LSCs，以消灭疾病。CXCL12 表达于骨髓龛中并控制 HSC 的维持，在此，我们发现，间质基质细胞 (MSCs) 中 CXCL12 的靶向缺失会减少正常 HSC 的数量，但通过增加自我更新细胞分裂来促进 LSC 的扩增，这可能是通过增强 EZH2 活性实现的。相比之下，内皮细胞特异性 CXCL12 缺失会减少 LSC 的增殖，表明龛位具有特异性效应。在 CML 发展过程中，异常聚集的 MSCs 和 LSCs 形成簇，但在 CXCL12 缺失时消失。此外，MSC 中 CXCL12 的特异性缺失会增加 TKI 治疗对 LSC 的消除。这些发现强调了 CXCL12 表达的龛位特异性效应在维持 TKI 耐药 LSC 群体静止中的关键作用。
