Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia.
Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia.
复制标题
DOI：
10.3390/cancers13225822
复制
发表时间：
2021-11-20
期刊：
影响因子：
5.2
通讯作者：
Ito K
中科院分区：
文献类型：
--
作者：
Ito K;Ito K
白血病干细胞是白血病细胞的一个罕见亚群，它不仅驱动白血病的发生和进展，而且还导致耐药性和/或疾病复发。为了实现永久治愈并防止复发，根除白血病干细胞至关重要。慢性粒细胞白血病是一种骨髓增生性疾病，酪氨酸激酶抑制剂显著改善了患者的长期预后和生活质量。BCR-ABL 1激酶结构域的点突变导致耐药性，因此，几种新一代酪氨酸激酶抑制剂已被引入临床。然而，一些患者在没有已知突变的情况下产生耐药性，并且白血病干细胞的存在被认为至少部分与耐药性发展和疾病复发相关。还探索了区分白血病干细胞与健康造血干细胞的特异性标志物的鉴定，以及骨髓微环境对白血病发病机制的潜在贡献。在这篇综述中，我们重新审视了目前的知识，白血病干细胞的作用，在药物治疗和探讨如何持久的治疗后，停止酪氨酸激酶抑制剂治疗可能实现无缓解。白血病干细胞（LSC，也称为白血病起始细胞）不仅驱动白血病的起始和进展，而且还有助于耐药性和/或疾病复发。因此，根除每一个最后的LSC对于患者的长期治愈至关重要。慢性粒细胞白血病（CML）是一种由多能造血干细胞和祖细胞引起的骨髓增生性疾病。酪氨酸激酶抑制剂（TKI）显著改善慢性期CML患者的长期结局和生活质量。BCR-ABL 1激酶结构域的点突变通过减少药物结合导致TKI耐药，因此，几种新一代TKI已被引入临床。然而，一些患者在没有已知突变的情况下出现TKI耐药，并且LSC的存在被认为至少部分与耐药发展和CML复发相关。我们先前提出靶向静止LSC作为CML的治疗方法，并且在过去十年中已经提出了许多靶向不敏感LSC的潜在策略。还探索了区分CML-LSC与健康HSC的特异性标志物的鉴定，以及骨髓微环境对CML发病机制的潜在贡献。尽管如此，预计仍有25%的CML患者至少转换一次TKI，各种TKI停药研究显示分子复发的发生率范围很广（从30%到60%）。在这篇综述中，我们回顾了目前关于LSC在CML白血病发生中的作用和对药物治疗的反应的知识，并探讨了在停止TKI治疗后如何实现和维持持久的无治疗缓解。
Leukemic stem cells represent a rare subpopulation of leukemic cells, which not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. To achieve permanent cures and prevent relapse, eradication of leukemia stem cells is essential. Chronic myeloid leukemia is a myeloproliferative disorder, and tyrosine kinase inhibitors have dramatically improved long-term outcomes and quality of life for patients. Point mutations of the kinase domain of BCR-ABL1 lead to drug resistance, and as a result, several new generations of tyrosine kinase inhibitor have been introduced to the clinic. Some patients develop drug resistance without known mutations, however, and the presence of leukemia stem cells is believed to be at least partially associated with resistance development and disease relapse. The identification of specific markers distinguishing leukemia stem cells from healthy hematopoietic stem cells, and the potential contributions of the bone marrow microenvironment to leukemia pathogenesis, have also been explored. In this review, we revisit the current knowledge regarding the roles of leukemia stem cells in response to pharmacological treatment and explore how durable treatment-free remission may be achieved after discontinuing tyrosine kinase inhibitor treatment. Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.
登录
查看更多内容
影响因子：
50.3
作者：
Gregory MA;Phang TL;Neviani P;Alvarez-Calderon F;Eide CA;O'Hare T;Zaberezhnyy V;Williams RT;Druker BJ;Perrotti D;Degregori J
通讯作者：
Degregori J
影响因子：
20.3
作者：
Grockowiak, Elodie;Laperrousaz, Bastien;Maguer-Satta, Veronique
通讯作者：
Maguer-Satta, Veronique
影响因子：
20.3
作者：
Agerstam, Helena;Hansen, Nils;Fioretos, Thoas
通讯作者：
Fioretos, Thoas
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
影响因子：
15.9
作者：
Carracedo, Arkaitz;Weiss, Dror;Pandolfi, Pier P.
通讯作者：
Pandolfi, Pier P.