Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.
Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.
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作者：
在急性白血病中，混合谱系白血病（MLL）基因被染色体易位破坏，产生一个与野生型基因相比具有改变特性的融合癌基因。小鼠功能丧失研究已经证明了Mll在发展造血系统中的重要作用，然而，使用不同的条件敲除模型的研究已经产生了关于成年稳态造血过程中对Mll的需求的相互矛盾的结果。在这里，我们使用一个loxp侧的Mll等位基因（MllF）和一个发育调节的、造血特异性的VavCre转基因来重新评估Mll丢失在造血谱系中的后果，而不需要Cre重组酶的诱导剂。我们展示了VavCre；Mll突变体表现出正常的胎儿造血功能，但很少能存活超过3周。存活的动物贫血，血小板减少，骨髓造血干细胞/祖细胞数量显著减少，与我们之前使用诱导型Mx1Cre转基因的发现一致。此外，对VavCre突变体的分析揭示了b淋巴生成中的其他缺陷，这些缺陷无法通过mx1cre介导的Mll缺失来评估。总的来说，这些数据支持Mll在维持出生后造血中起重要作用的结论。
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 demonstrated 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. Here, we employ a loxP-flanked Mll allele (MllF) and a developmentally-regulated, haematopoietic-specific VavCre transgene to re-assess 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 plays an essential role in sustaining postnatal haematopoiesis.
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