Leukemia stem cells in a genetically defined murine model of blast-crisis CML
Leukemia stem cells in a genetically defined murine model of blast-crisis CML
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DOI：
10.1182/blood-2007-02-073031
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Jordan, Craig T.
中科院分区：
文献类型：
--
作者：
Neering, Sarah J.;Bushnell, Timothy;Jordan, Craig T.
髓系白血病起源于白血病干细胞（LSCs），它对标准化疗药物具有耐药性，可能是耐药疾病和复发的主要原因。为了研究LSCs的体内特性，我们建立了一个小鼠模型，其中人类LSCs的生物学特征被密切模仿。对原始正常造血细胞进行修饰，表达BCR/ABL和Nup981HoxA9易位产物，并鉴定出具有谱系（-）、Kit（+/-）、Flt3（+）、Sca（+）、CD34（+）和CD150（-）异常免疫表型的独特LSC群体。然后进行体内研究以评估LSCs对治疗性损伤的反应。用ABL激酶抑制剂甲磺酸伊马替尼治疗动物诱导了母细胞和祖细胞的特异性调节，而不是干细胞群，从而概括了推断发生在人类慢性粒细胞白血病（CML）患者中的事件。此外，白血病小鼠全身照射对正常造血干细胞（HSCs）具有选择性毒性，表明LSCs在体内具有抗凋亡和/或衰老的能力。综上所述，该系统提供了一种强大的手段，通过该手段可以表征LSCs与hsc的体内行为，并且可以优化候选治疗方案，以最大程度地特异性针对原始白血病细胞。
Myeloid leukemia arises from leukemia stem cells (LSCs), which are resistant to standard chemotherapy agents and likely to be a major cause of drug-resistant disease and relapse. To investigate the in vivo properties of LSCs, we developed a mouse model in which the biologic features of human LSCs are closely mimicked. Primitive normal hematopoietic cells were modified to express the BCR/ABL and Nup981HoxA9 translocation products, and a distinct LSC population, with the aberrant immunophenotype of lineage(-), Kit(+/-), Flt3(+), Sca(+), CD34(+), and CD150(-), was identified. In vivo studies were then performed to assess the response of LSCs to therapeutic insult. Treatment of animals with the ABL kinase inhibitor imatinib mesylate induced specific modulation of blasts and progenitor cells but not stem-cell populations, thereby recapitulating events inferred to occur in human chronic myelogenous leukemia (CML) patients. In addition, challenge of leukemic mice with total body irradiation was selectively toxic to normal hematopoietic stem cells (HSCs), suggesting that LSCs are resistant to apoptosis and/or senescence in vivo. Taken together, the system provides a powerful means by which the in vivo behavior of LSCs versus HSCs can be characterized and candidate treatment regimens can be optimized for maximal specificity toward primitive leukemia cells.