PDF(Pubmed)
Abstract：
Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence.
Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers.
Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.
Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers.
Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.
摘要：
背景：利用癌细胞脆弱性的靶向治疗有望改善患者预后并减少化疗的副作用。然而,精准治疗的疗效有限，部分原因是肿瘤细胞异质性。更好地理解药物作用如何与癌细胞状态多样性相关联对于确定可以预防疾病复发的有效组合疗法至关重要。
结果：这里，我们描述了G2/M检查点抑制在急性淋巴细胞白血病(ALL)中的作用,并证明了WEE1靶向治疗对细胞命运决定调节回路的影响.我们发现KMT2A重排对ALL细胞增殖恢复的抑制作用最高。RS4的单细胞RNA-seq和ATAC-seq;11个带有KMT2A::AFF1的细胞，用WEE1抑制剂AZD1775处理，揭示细胞状态的多样化，部分细胞表现出与细胞凋亡和衰老相关的p53驱动过程的强烈激活，以及核心KMT2A-RUNX1-MYC监管网络的中断。在这种由WEE1抑制诱导的细胞状态多样化中，亚群过渡到药物耐受性细胞状态，其特征是转录因子的激活调节前B细胞命运，脂质代谢，和以可逆方式的前BCR信号传导。BCR信号抑制剂达沙替尼的序贯治疗，伊布替尼,或通过fatostatin或AZD2014干扰代谢通过诱导细胞死亡和抑制干性标志物有效抵消药物耐受性。
结论：总的来说，我们的研究结果为与细胞周期和细胞命运调控相关的基因调控程序的紧密连接提供了新的见解，和顺序给药WEE1抑制剂与前BCR信号或代谢的低毒性抑制剂的基本原理。
结果：这里，我们描述了G2/M检查点抑制在急性淋巴细胞白血病(ALL)中的作用,并证明了WEE1靶向治疗对细胞命运决定调节回路的影响.我们发现KMT2A重排对ALL细胞增殖恢复的抑制作用最高。RS4的单细胞RNA-seq和ATAC-seq;11个带有KMT2A::AFF1的细胞，用WEE1抑制剂AZD1775处理，揭示细胞状态的多样化，部分细胞表现出与细胞凋亡和衰老相关的p53驱动过程的强烈激活，以及核心KMT2A-RUNX1-MYC监管网络的中断。在这种由WEE1抑制诱导的细胞状态多样化中，亚群过渡到药物耐受性细胞状态，其特征是转录因子的激活调节前B细胞命运，脂质代谢，和以可逆方式的前BCR信号传导。BCR信号抑制剂达沙替尼的序贯治疗，伊布替尼,或通过fatostatin或AZD2014干扰代谢通过诱导细胞死亡和抑制干性标志物有效抵消药物耐受性。
结论：总的来说，我们的研究结果为与细胞周期和细胞命运调控相关的基因调控程序的紧密连接提供了新的见解，和顺序给药WEE1抑制剂与前BCR信号或代谢的低毒性抑制剂的基本原理。
