PHF6在AML中抑制白血病干细胞的自我更新

PHF6 suppresses self-renewal of leukemic stem cells in AML

LEUKEMIA

影响因子:13.4

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

DOI: 10.1038/s41375-024-02340-5

摘要

急性髓系白血病（AML）以自我更新的髓系祖细胞的无限增殖伴随分化阻滞为特征。PHF6是一种染色质结合蛋白，在髓系白血病中发生突变，其孤立缺失可增加小鼠造血干细胞（HSC）的自我更新，但不引发恶性转化。我们报道，Phf6敲除增强Hoxa9驱动的AML的侵袭性，尤其在连续移植中，以及增加白血病起始细胞（LIC）的频率。我们定义了Hoxa9驱动AML的体内层级结构，并识别出一种被称为“LIC-e”的富集白血病起始细胞群体。研究发现，Phf6缺失扩大了LIC-e群体，并使其转录组偏向更具干细胞特征的状态；在人类AML细胞系和BEAT AML患者样本中，PHF6突变也表现出相似的转录组变化。我们证明，Phf6缺失引起的LIC-e积累并非通过影响细胞周期或凋亡，而是由于其后代中保持LIC-e身份的细胞比例增加。我们的工作表明，Phf6缺失通过在白血病干细胞中的特异性作用，增强AML的自我更新能力。

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.