Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
Leukemia. 2010 Oct;24(10):1732-41. doi: 10.1038/leu.2010.171. Epub 2010 Aug 19.
The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.
混合谱系白血病（MLL）基因在急性白血病中通过染色体易位被破坏，产生具有改变性质的融合癌基因，相对于野生型基因。鼠类缺失功能研究表明 Mll 在造血系统发育中具有重要作用，但使用不同的条件性敲除模型进行的研究对于在成年稳态造血过程中 Mll 的需求产生了相互矛盾的结果。在这项研究中，我们使用了一个loxP 侧翼的 Mll 等位基因（Mll(F)）和一个发育调控的、造血特异性的 VavCre 转基因，在不需要 Cre 重组酶诱导剂的情况下，重新评估 Mll 在造血谱系中的缺失后果。我们表明，VavCre;Mll 突变体表现出表型正常的胎儿造血，但很少能存活超过 3 周。幸存的动物贫血、血小板减少，并表现出骨髓造血干细胞/祖细胞群体的显著减少，与我们之前使用诱导型 Mx1Cre 转基因的研究结果一致。此外，VavCre 突变体的分析揭示了 B 淋巴细胞生成中的其他缺陷，这些缺陷无法使用 Mx1Cre 介导的 Mll 缺失来评估。总之，这些数据支持 Mll 在维持出生后造血中具有重要作用的结论。
