Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice.
Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice.
复制标题
作者：
Hyde RK;Zhao L;Alemu L;Liu PP
cbf - β- smmhc是由16号染色体倒置融合基因CBFB-MYH11产生的融合蛋白，已知可引发白血病的发生。然而，CBFβ-SMMHC促进白血病发展的机制尚不清楚。以前有人提出CBFβ-SMMHC主要抑制转录因子RUNX1，但我们最近发现CBFβ-SMMHC具有独立于RUNX1抑制的活性。此外，我们还发现，RUNX1结合活性降低的修饰的CBFβ-SMMHC加速了白血病的发生。这些结果提出了RUNX1在cbf - β- smmhc白血病发生中的重要性的问题。为了验证这一点，我们在Runx1缺陷背景下产生了表达Cbfb-MYH11的小鼠，由纯合子Runx1零等位基因（Runx1−/−）或单个显性阴性Runx1等位基因（Runx1+/lz）引起。我们发现Runx1活性的缺失挽救了Cbfb-MYH11在原始造血过程中诱导的分化缺陷。在最终的造血过程中，RUNX1的缺失也显著降低了Cbfb-MYH11诱导的增殖和分化缺陷。重要的是，Cbfb-MYH11诱导的白血病在Runx1+/lz小鼠中比在Runx1充足小鼠中具有更长的潜伏期。这些数据表明Runx1活性对于Cbfb-MYH11诱导的造血缺陷和白血病发生至关重要。
CBFβ-SMMHC, the fusion protein generated by the chromosome 16 inversion fusion gene, CBFB-MYH11, is known to initiate leukemogenesis. However, the mechanism through which CBFβ-SMMHC contributes to leukemia development is not well understood. Previously it was proposed that CBFβ-SMMHC acts by dominantly repressing the transcription factor RUNX1, but we recently showed that CBFβ-SMMHC has activities that are independent of RUNX1 repression. In addition, we showed that a modified CBFβ-SMMHC with decreased RUNX1 binding activity accelerates leukemogenesis. These results raise questions about the importance of RUNX1 in leukemogenesis by CBFβ-SMMHC. To test this, we generated mice expressing Cbfb-MYH11 in a Runx1 deficient background, resulting from either homozygous Runx1 null alleles (Runx1−/−) or a single dominant negative Runx1 allele (Runx1+/lz). We found that loss of Runx1 activity rescued the differentiation defects induced by Cbfb-MYH11 during primitive hematopoiesis. During definitive hematopoiesis, RUNX1 loss also significantly reduced the proliferation and differentiation defects induced by Cbfb-MYH11. Importantly, Cbfb-MYH11 induced leukemia had much longer latency in Runx1+/lz mice than in Runx1 sufficient mice. These data indicate that Runx1 activity is critical for Cbfb-MYH11 induced hematopoietic defects and leukemogenesis.