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Abstract：
The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.
摘要：
由于缺乏合适的小鼠模型，对急性髓细胞性白血病（AML）p53突变背后的机制的研究受到限制。历史上导致淋巴瘤而不是白血病。本研究介绍了两种新的AML小鼠模型。一个模型在早期发育中诱导突变型p53和Mdm2单倍体不足，显示Mdm2在骨髓偏向造血和AML易感性中的作用，独立于p53第二个模型通过在成人造血干细胞中诱导突变型p53来模拟克隆造血，证明p53突变的时间决定了AML与淋巴瘤的发展。在这种情况下，与年龄相关的造血干细胞(HSCs)的改变与突变型p53共同作用,导致髓样转化而不是淋巴瘤的发生.我们的研究揭示了HSC年龄合作影响的新见解，Trp53突变,和Mdm2单倍体不足对克隆造血和骨髓恶性肿瘤的发展。
