PHF6抑制AML中白血病干细胞的自我更新
PHF6 suppresses self-renewal of leukemic stem cells in AML
影响因子:13.40000
分区:医学1区 Top / 血液学1区 肿瘤学2区
发表日期:2024 Sep
作者:
Sapana S Jalnapurkar, Aishwarya S Pawar, Subin S George, Charles Antony, Patrick Somers, Jason Grana, Victoria K Feist, Sandeep Gurbuxani, Vikram R Paralkar
摘要
急性髓细胞性白血病的特征是自我更新的髓样祖细胞不受控制，并伴有分化停滞。 PHF6是一种在髓样白血病中突变的染色质结合蛋白，其孤立损失会增加小鼠HSC自我更新而没有恶性转化。我们在这里报告说，PHF6敲除增加了HOXA9驱动的AML在串行移植上的攻击性，并增加了白血病启动细胞的频率。我们定义了由HOXA9驱动的AML的体内层次结构，并确定了我们称为“ LIC-E”（白血病启动富集细胞）种群的人群。我们发现，PHF6损失将LIC-E人口扩大，并将其转录组偏向更类似的状态。在人AML细胞系中的PHF6基因敲除以及BEAT AML数据集中的PHF6突变患者样品中，还观察到一致的转录组移位。我们证明，LIC-E在PHF6基因敲除AML中的积累并不是由于对细胞周期或凋亡的影响，而是由于其后代的比例增加而保留LIC-E身份。我们的工作表明，PHF6损失通过对白血病干细胞的上下文特异性影响增加了AML自我更新。
Abstract
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.