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CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy.
Leukemia ( IF 12.8 ) Pub Date : 2020-01-02 , DOI: 10.1038/s41375-019-0684-5
Ross Kinstrie 1 , Gillian A Horne 1 , Heather Morrison 1 , David Irvine 1 , Chinmay Munje 1 , Eduardo Gómez Castañeda 1 , Hothri A Moka 1 , Karen Dunn 1 , Jennifer E Cassels 1 , Narissa Parry 1 , Cassie J Clarke 1 , Mary T Scott 1 , Richard E Clark 2 , Tessa L Holyoake 1 , Helen Wheadon 1 , Mhairi Copland 1
Affiliation  

The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin-CD34+CD38-CD90+ CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93- CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin-CD34+CD38-CD90+ CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.

中文翻译:

CD93 在慢性髓性白血病干细胞上表达,并确定在酪氨酸激酶抑制剂治疗后持续存在的静止群体。

BCR-ABL 酪氨酸激酶抑制剂的引入彻底改变了慢性粒细胞白血病 (CML) 的治疗。一个主要的临床目标仍然是识别和消除低水平的疾病持续性,称为“最小残留疾病”。疾病持续存在的现象表明,尽管有针对性的治疗方法,但存在维持白血病干细胞 (LSC) 存活的不依赖 BCR-ABL 的机制。尽管已在临床前环境中鉴定了原始 CML LSC 群体的其他标志物,但似乎只有 CD26 可提供临床效用。在这里,我们证明了 CD93 在 lin-CD34+CD38-CD90+ CML LSC 群体上的一致和选择性表达,并显示体外和体内数据表明干细胞特征增加,以及与无法移植的 CD93-CML 干/祖细胞群相比,在患者衍生的异种移植模型中的稳健移植。通过对选定的干细胞和细胞存活特异性基因进行批量和单细胞分析,我们证实了静止特征,并证明了它们在一组 CML 患者样本中的持久性,这些样本在 TKI 戒断时表现出分子复发。总之,我们的结果表明,CD93 在具有干细胞特征的 lin-CD34+CD38-CD90+ CML LSC 群体上持续且选择性地表达,并且可能是确定 TKI 反应不佳的重要指标。我们证实了静止特征并在一组 CML 患者样本中证明了它们的持久性,这些样本在 TKI 撤药时表现出分子复发。总之,我们的结果表明,CD93 在具有干细胞特征的 lin-CD34+CD38-CD90+ CML LSC 群体上持续且选择性地表达,并且可能是确定 TKI 反应不佳的重要指标。我们证实了静止特征并在一组 CML 患者样本中证明了它们的持久性,这些样本在 TKI 撤药时表现出分子复发。总之,我们的结果表明,CD93 在具有干细胞特征的 lin-CD34+CD38-CD90+ CML LSC 群体上持续且选择性地表达,并且可能是确定 TKI 反应不佳的重要指标。
更新日期:2020-01-02
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