Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells
Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells
复制标题
小鼠急性白血病的发展独立于造血干细胞和祖细胞的自我更新和分化潜力。
DOI：
10.1182/bloodadvances.2018022400
复制
发表时间：
2019
期刊：
影响因子：
7.5
通讯作者：
Hideo Ema
中科院分区：
文献类型：
--
作者：
Fang Dong;Haitao Bai;Xiaofang Wang;Shanshan Zhang;Zhao Wang;Miner Xie;Sen Zhang;Jinhong Wang;Sha Hao;Tao Cheng;Hideo Ema
起源细胞定义为转化事件首先发生的正常细胞，尽管其在理解白血病发生和改善白血病治疗中的重要性，但在白血病中识别不佳。虽然造血干细胞（HSCs）和造血祖细胞（HPCs）被用于白血病模型，但它们的自我更新和分化潜能是否影响白血病的发生和发展在很大程度上是未知的。在这项研究中，两种不同类型的HSC的自我更新和分化潜能（HSC 1 [CD 150 + CD 41-CD 34-谱系-Sca-1+c-Kit+细胞]和HSC 2 [CD 150-CD 41-CD 34-谱系-Sca-1+c-Kit+细胞]）和3种不同类型的HPC（HPC 1 [CD 150 + CD 41 + CD 34-谱系-Sca-1+c-Kit+细胞]、HPC 2 [CD 150 + CD 41 + CD 34+谱系-Sca-1+c-Kit+细胞]和HPC 3 [CD 150-CD 41-CD 34+谱系-Sca-1+c-Kit+细胞]）从成年小鼠骨髓中分离，并通过竞争性再增殖测定进行检测。然后，将来自每个群体的细胞逆转录病毒转导以引发MLL-AF 9急性髓性白血病（AML）和NOTCH-1 T细胞急性淋巴细胞白血病（T-ALL）的细胞内结构域。AML和T-ALL类似地从所有HSC和HPC群体发展，表明白血病的多细胞起源。在这些AML和T-ALL模型中还鉴定了新的白血病干细胞（LSC）。值得注意的是，观察到免疫表型不成熟和成熟LSC之间的转换，表明异质性LSC在白血病的扩增和维持中发挥作用。基于该小鼠模型研究，我们提出急性白血病起源于多个起源细胞，独立于造血干细胞和祖细胞的自我更新和分化潜能，并通过LSC扩增。
The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of leukemogenesis and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 [CD150+CD41-CD34-Lineage-Sca-1+c-Kit+ cells] and HSC2 [CD150-CD41-CD34-Lineage-Sca-1+c-Kit+ cells]) and 3 distinct types of HPCs (HPC1 [CD150+CD41+CD34-Lineage-Sca-1+c-Kit+ cells], HPC2 [CD150+CD41+CD34+Lineage-Sca-1+c-Kit+ cells], and HPC3 [CD150-CD41-CD34+Lineage-Sca-1+c-Kit+ cells]) were isolated from adult mouse bone marrow, and examined by competitive repopulation assay. Then, cells from each population were retrovirally transduced to initiate MLL-AF9 acute myelogenous leukemia (AML) and the intracellular domain of NOTCH-1 T-cell acute lymphoblastic leukemia (T-ALL). AML and T-ALL similarly developed from all HSC and HPC populations, suggesting multiple cellular origins of leukemia. New leukemic stem cells (LSCs) were also identified in these AML and T-ALL models. Notably, switching between immunophenotypical immature and mature LSCs was observed, suggesting that heterogeneous LSCs play a role in the expansion and maintenance of leukemia. Based on this mouse model study, we propose that acute leukemia arises from multiple cells of origin independent of the self-renewal and differentiation potentials in hematopoietic stem and progenitor cells and is amplified by LSC switchover.