骨髓微环境的表征在慢性髓细胞白血病患者中鉴定出CXCL14作为一种新的治疗选项。
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option.
发表日期：2023 Apr 05
作者：
Monika Dolinska, Huan Cai, Alma Mansson, Jingyi Shen, Pingnan Xiao, Thibault Bouderlique, Xidan Li, Elory Leonard, Marcus Chang, Yuchen Gao, Juan Pablo Medina Giménez, Makoto Kondo, Lakshmi Sandhow, Anne-Sofie Johansson, Stefan Deneberg, Stina Söderlund, Martin Jädersten, Johanna S Ungerstedt, Magnus Tobiasson, Arne Östman, Satu Mustjoki, Leif Stenke, Katarina Le Blanc, Eva S Hellstrom-Lindberg, Sören Lehmann, Marja Ekblom, Ulla Olsson-Strömberg, Mikael Sigvardsson, Hong Qian
来源：
BLOOD
摘要：
尽管酪氨酸激酶抑制剂对治疗慢性髓细胞白血病（CML）有效，但往往无法根除引发CML的干细胞（LSC），导致疾病持续和复发。证据表明，LSC持续存在可能是由于骨髓（BM）基质的保护作用。然而，对其潜在机制知之甚少。我们在此分子和功能上表征了CML患者诊断时的BM基质，并揭示了CML患者基质组成和功能的改变。长期培养启动细胞（LTC-IC）实验显示，来自CML患者的骨髓基质干细胞显示出对正常和CML BM CD34 + CD38-细胞的增强支持能力。从分子上看，RNA测序检测到CML患者BM细胞基质中细胞因子和生长因子表达失调。其中，CXCL14在BM细胞基质中丧失，而在健康的BM中则有表达。恢复CXCL14可以显著抑制CML LSC的维持，并增强它们对伊马替尼的反应，且能在NSG-SGM3小鼠的体内移植CML。重要的是，CXCL14治疗大大抑制了移植的NSG-SGM3小鼠中的CML移植，甚至比伊马替尼更为显著，并且这种抑制在对TKI反应不佳的患者中持续存在。在机械学上，CXCL14升高了CML LSC中的炎症因子信号转导，但降低了mTOR信号转导和氧化磷酸化水平。综上所述，我们发现了CXCL14在CML LSC生长中的抑制作用。CXCL14可能提供针对CML LSC的治疗选择。Copyright © 2023 American Society of Hematology.
Although tyrosine kinase inhibitors are effective for treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be due to bone marrow (BM) niche protection. However, little is known about the underlying mechanisms. We here molecularly and functionally characterized BM niches in CML patients at diagnosis and revealed the altered niche composition and function in the CML patients. Long-term culture initiating cell (LTC-IC) assay showed that the mesenchymal stem cells from CML patients displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in CML patient BM cellular niches. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.Copyright © 2023 American Society of Hematology.