急性髓系白血病 (AML) 源自白血病前期病症。我们研究了典型的白血病前期、骨髓增生性肿瘤和克隆性造血的发病机制。两种白血病前期条件下的造血干细胞都存在反复的驱动突变；额外的突变会引发进一步的恶性转化，导致 AML 的发生。尽管遗传改变被定义为恶性转化的主要原因，但非遗传因素也参与疾病进展。在这篇综述中，我们重点关注非组蛋白染色质蛋白、高迁移率基团 AT-hook2 (HMGA2) 和生理性 p53 抑制剂、鼠双分钟 X (MDMX)。 HMGA2 主要因 microRNA 失调或多梳成分突变而过度表达，并通过干细胞特征破坏引发白血病前期克隆的扩增。 MDMX 在骨髓恶性肿瘤中因剪接平衡改变而过度表达。 MDMX 通过抑制 p53 和 p53 独立的 WNT/β-catenin 信号传导激活来诱导白血病前期的白血病转化。我们还讨论了如何针对这些非遗传因素进行白血病预防治疗。

Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/β-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.