Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines
Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines
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DOI：
10.1182/bloodadvances.2017004903
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发表时间：
2017-06-13
期刊：
影响因子：
7.5
通讯作者：
Louache, Fawzia
中科院分区：
文献类型：
--
作者：
Zhang, Yanyan;He, Liang;Louache, Fawzia
慢性粒单核细胞白血病（CMML）是一种克隆性造血干细胞疾病，通常与表观遗传、剪接和信号传导基因的突变有关。转基因小鼠模型仅部分重现疾病表型，而CMML细胞在免疫功能低下小鼠中的异种移植迄今为止很少成功。在此，将从患者骨髓（BM）或外周血（PB）中分选的CMML CD 34（+）细胞静脉内注射到NSG（NOD/LtSz-scid IL 2 r γ null）小鼠和经工程改造以表达人粒单核细胞集落刺激因子、干细胞因子和白细胞介素-3的NSG小鼠（NSGS小鼠）中。16份患者样本中有15份（94%）成功植入NSG或NSGS或两种小鼠品系。人细胞的扩增（主要在BM中）也在脾脏和PB中观察到，并且在产生3种人细胞因子的小鼠中大大增强。在移植细胞中鉴定的基因突变大多与注射前在患者细胞中鉴定的基因突变相似。在NSGS小鼠中，10次尝试中有3次获得成功的二次植入。因此，原代CMML白血病细胞在NSGS中的扩增比NSG小鼠好得多，二次移植的效果有限。
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34(+) cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2r gamma null) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant.