Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Biomedical Graduate Studies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Leukemia. 2024 Sep;38(9):1938-1948. doi: 10.1038/s41375-024-02340-5. Epub 2024 Jul 14.
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，并伴有分化阻滞。PHF6 是一种在髓系白血病中发生突变的染色质结合蛋白，其单独缺失会增加小鼠 HSC 的自我更新而不发生恶性转化。我们在这里报告，Phf6 缺失会增加 Hoxa9 驱动的 AML 在连续移植中的侵袭性，并增加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，并鉴定出一个我们称之为“LIC-e”（富含白血病起始细胞）的群体。我们发现 Phf6 缺失会扩大 LIC-e 群体，并使其转录组向更类似于干细胞的状态倾斜；在人类 AML 细胞系和 BEAT AML 数据集的 PHF6 突变患者样本中也观察到 PHF6 缺失的一致转录组变化。我们证明，Phf6 缺失的 AML 中 LIC-e 的积累不是由于对细胞周期或凋亡的影响，而是由于其后代中保留 LIC-e 特征的部分增加。我们的工作表明，Phf6 缺失通过对白血病干细胞的特定于上下文的影响增加了 AML 的自我更新。
