Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the “LIC-e” (leukemia initiating cells enriched) population. We find that Phf6 loss expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.

急性髓系白血病的特征是自我更新的髓系祖细胞不受控制的增殖并伴有分化停滞。 PHF6是一种在髓性白血病中发生突变的染色质结合蛋白，其单独缺失可增加小鼠HSC的自我更新而不会发生恶性转化。我们在此报告， Phf6敲除增加了Hoxa9驱动的 AML 相对于连续移植的侵袭性，并增加了白血病起始细胞的频率。我们定义了Hoxa9驱动的 AML 的体内层次结构，并确定了一个称为“LIC-e”（白血病起始细胞富集）群体的群体。我们发现Phf6损失扩大了 LIC-e 群体，并将其转录组偏向更像茎的状态；在人类 AML 细胞系中的PHF6敲除以及 BEAT AML 数据集中的PHF6突变患者样本中也观察到了一致的转录组变化。我们证明Phf6敲除 AML 中 LIC-e 积累的发生并不是由于对细胞周期或细胞凋亡的影响，而是由于保留 LIC-e 身份的后代比例的增加。我们的工作表明Phf6缺失通过对白血病干细胞的特定情况影响来增强 AML 的自我更新。