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在人类肥大细胞白血病中鉴定白血病起始干细胞。

Identification of a leukemia-initiating stem cell in human mast cell leukemia.

机构信息

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090, Vienna, Austria.

出版信息

Leukemia. 2019 Nov;33(11):2673-2684. doi: 10.1038/s41375-019-0460-6. Epub 2019 Apr 5.

DOI:10.1038/s41375-019-0460-6
PMID:30953030
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6839966/
Abstract

Mast cell leukemia (MCL) is a highly fatal malignancy characterized by devastating expansion of immature mast cells in various organs. Although considered a stem cell disease, little is known about MCL-propagating neoplastic stem cells. We here describe that leukemic stem cells (LSCs) in MCL reside within a CD34/CD38 fraction of the clone. Whereas highly purified CD34/CD38 cells engrafted NSG mice with fully manifesting MCL, no MCL was produced by CD34/CD38 progenitors or the bulk of KIT/CD34 mast cells. CD34/CD38 MCL cells invariably expressed CD13 and CD133, and often also IL-1RAP, but did not express CD25, CD26 or CLL-1. CD34/CD38 MCL cells also displayed several surface targets, including CD33, which was homogenously expressed on MCL LSCs in all cases, and the D816V mutant form of KIT. Although CD34/CD38 cells were resistant against single drugs, exposure to combinations of CD33-targeting and KIT-targeting drugs resulted in LSC-depletion and markedly reduced engraftment in NSG mice. Together, MCL LSCs are CD34/CD38 cells that express distinct profiles of markers and target antigens. Characterization of MCL LSCs should facilitate their purification and should support the development of LSC-eradicating curative treatment approaches in this fatal type of leukemia.

摘要

肥大细胞白血病（MCL）是一种高度致命的恶性肿瘤，其特征是不成熟的肥大细胞在各种器官中破坏性地扩张。尽管被认为是一种干细胞疾病，但对促进 MCL 的肿瘤性干细胞知之甚少。我们在这里描述，MCL 中的白血病干细胞（LSC）存在于克隆的 CD34/CD38 部分内。虽然高度纯化的 CD34/CD38 细胞可将 NSG 小鼠植入具有完全表现出的 MCL，但 CD34/CD38 祖细胞或大量 KIT/CD34 肥大细胞均未产生 MCL。CD34/CD38 MCL 细胞始终表达 CD13 和 CD133，并且通常还表达 IL-1RAP，但不表达 CD25、CD26 或 CLL-1。CD34/CD38 MCL 细胞还显示出几个表面靶标，包括在所有情况下均均匀表达于 MCL LSC 的 CD33，以及 KIT 的 D816V 突变形式。尽管 CD34/CD38 细胞对单药具有抗性，但暴露于 CD33 靶向和 KIT 靶向药物的组合中会导致 LSC 耗竭，并显着减少 NSG 小鼠的植入。总之，MCL LSC 是表达独特标志物和靶抗原的 CD34/CD38 细胞。MCL LSC 的表征应有助于其纯化，并应支持在这种致命类型的白血病中开发消除 LSC 的治愈性治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/1656de1946ec/emss-82267-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/af5ce973a207/emss-82267-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/07c5713e3ad5/emss-82267-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/1656de1946ec/emss-82267-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/af5ce973a207/emss-82267-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/07c5713e3ad5/emss-82267-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee80/6839966/1656de1946ec/emss-82267-f003.jpg

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