CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia.
CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia.
复制标题
DOI：
10.1016/j.stem.2015.08.008
复制
发表时间：
2015-10-01
期刊：
影响因子：
23.9
通讯作者：
Cleary ML
中科院分区：
文献类型：
--
作者：
Iwasaki M;Liedtke M;Gentles AJ;Cleary ML
白血病干细胞（LSCs）被认为与造血干细胞具有一些共同的特性，包括细胞周期静止和自我更新的能力。据推测，这些特征是白血病发生、进展和复发的基础，也使通过治疗靶向LSCs而不对hsc产生不良影响来根除白血病的努力复杂化。在这里，我们表明急性髓系白血病与MLL基因的基因组重排包含一个非静止LSC群体。虽然人类CD34+CD38−LSCs通常是高度静止的，但c型凝集素CD93在活跃循环的非静止AML细胞亚群上表达，这些细胞具有丰富的LSC活性。CD93的表达在功能上是原发人AML LSCs植入和白血病发生所必需的，并且主要通过沉默AML中的主要肿瘤抑制因子CDKN2B来调节LSC的自我更新。因此，CD93的表达在mll重排的AML中确定了一个主要循环的、非静止的白血病启动细胞群，为选择性靶向和根除LSCs提供了机会。
Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells, including cell cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34+CD38− LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs.