Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia
Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia
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DOI：
10.1182/blood-2010-12-322230
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发表时间：
2011-05-05
期刊：
影响因子：
20.3
通讯作者：
Menendez, Pablo
中科院分区：
文献类型：
--
作者：
Montes, Rosa;Ayllon, Veronica;Menendez, Pablo
婴儿急性淋巴细胞白血病携带融合混合系白血病（MLL）-AF 4与预后不良和非常短暂的潜伏期有关。我们对MLL-AF 4转化的有限理解反映在小鼠模型中，其不能准确地再现人类疾病。MLL-AF 4疾病的人类模型不存在。造血干细胞或祖细胞（HSPC）是转化的可能靶点。在此，我们在体外和体内探索了MLL-AF 4在人脐带血来源的CD 34（+）HSPC中的强制表达的影响。向NOD/SCID-IL 2 R γ（-/-）小鼠的骨髓内移植揭示了在MLL-AF 4的强制表达下增强的多谱系造血移植、效率和向其他造血位点的归巢。慢病毒介导MLL-AF 4转染CD 34（+）HSPCs可提高CD 34（+）祖细胞的体外克隆形成能力并促进其增殖。因此，细胞周期和细胞凋亡分析表明，MLL-AF 4传达了选择性增殖耦合到生存优势，这与参与细胞凋亡，传感DNA损伤和DNA修复的基因表达的变化相关。然而，MLL-AF 4表达不足以单独启动白血病发生，表明启动ALL可能需要额外的命中（或AF 4-MLL相互产物），或者脐带血来源的CD 34（+）HSPC不是MLL-AF 4介导的ALL的适当细胞靶点。（血。2011; 117（18）：4746-4758）
Infant acute lymphoblastic leukemia harboring the fusion mixed-lineage leukemia (MLL)-AF4 is associated with a dismal prognosis and very brief latency. Our limited understanding of transformation by MLL-AF4 is reflected in murine models, which do not accurately recapitulate the human disease. Human models for MLL-AF4 disease do not exist. Hematopoietic stem or progenitor cells (HSPCs) represent probable targets for transformation. Here, we explored in vitro and in vivo the impact of the enforced expression of MLL-AF4 in human cord blood-derived CD34(+) HSPCs. Intrabone marrow transplantation into NOD/SCID-IL2R gamma(-/-) mice revealed an enhanced multilineage hematopoietic engraftment, efficiency, and homing to other hematopoietic sites on enforced expression of MLL-AF4. Lentiviral transduction of MLL-AF4 into CD34(+) HSPCs increased the in vitro clonogenic potential of CD34(+) progenitors and promoted their proliferation. Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. However, MLL-AF4 expression was insufficient to initiate leukemogenesis on its own, indicating that either additional hits (or reciprocal AF4-MLL product) may be required to initiate ALL or that cord blood-derived CD34(+) HSPCs are not the appropriate cellular target for MLL-AF4-mediated ALL. (Blood. 2011; 117(18): 4746-4758)