文章：

在免疫缺陷小鼠中建模慢性粒细胞白血病，揭示异常肥大细胞的扩增和前B细胞的积聚

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

原文发布日期：2014-12-12

DOI: 10.1038/bcj.2014.89

类型: Original Article

开放获取: 是

英文摘要：

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34+ cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.

摘要翻译： 

慢性粒细胞白血病（CML）是一种骨髓增殖性肿瘤，若不治疗将进展为髓系或B淋巴表型的急变期（BC）。编码持续活性酪氨酸激酶的BCR-ABL1融合基因被认为是诱发慢性期（CP）CML的充分条件，而进展至CML急变期则需要其他遗传病变的参与。为构建人源化CML模型，我们在脐带血CD34+细胞中通过逆转录病毒表达BCR-ABL1，并将其移植至NOD-SCID（非肥胖糖尿病/重症联合免疫缺陷）IL-2受体γ缺陷型小鼠体内。在初代移植小鼠中，BCR-ABL1表达诱导了骨髓和脾脏的炎症样状态，肥大细胞成为BCR-ABL1特异性扩增的唯一髓系谱系。经过二次移植后，显著的炎症表型消失，骨髓中主要存在人源肥大细胞和巨噬细胞。此外，在初代小鼠中观察到前B细胞阶段的显著阻滞，导致前B细胞积聚。在CML患者的原代细胞中亦可证实类似的B细胞分化阻滞。因此，该人源化CML小鼠模型揭示了慢性期CML此前未被探索的特征，有助于进一步研究CML的发病机制。

原文链接：

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells