PDF(Pubmed)
Abstract：
UNASSIGNED: Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia and atypical chronic myeloid leukemia. Although inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to the cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a proapoptotic response. Consequently, malignancies reliant on elevated MAPK signaling use MAPK feedback regulators to intricately modulate the signaling output, prioritizing proliferation and survival while dampening the apoptotic stimuli. Herein, we demonstrate that enhanced MAPK signaling in granulocyte colony-stimulating factor 3 receptor (CSF3R)-driven leukemia upregulates the expression of dual specificity phosphatase 1 (DUSP1) to suppress the apoptotic stimuli crucial for leukemogenesis. Consequently, genetic deletion of Dusp1 in mice conferred synthetic lethality to CSF3R-induced leukemia. Mechanistically, DUSP1 depletion in leukemic context causes activation of JNK1/2 that results in induced expression of BIM and P53 while suppressing the expression of BCL2 that selectively triggers apoptotic response in leukemic cells. Pharmacological inhibition of DUSP1 by BCI (a DUSP1 inhibitor) alone lacked antileukemic activity due to ERK1/2 rebound caused by off-target inhibition of DUSP6. Consequently, a combination of BCI with a MEK inhibitor successfully cured CSF3R-induced leukemia in a preclinical mouse model. Our findings underscore the pivotal role of DUSP1 in leukemic transformation driven by enhanced MAPK signaling and advocate for the development of a selective DUSP1 inhibitor for curative treatment outcomes.
摘要：
升高的MAPK和JAK-STAT信号在慢性中性粒细胞白血病（CNL）和非典型慢性粒细胞白血病（aCML）的发病机制中起关键作用。虽然靶向这些途径的抑制剂有效抑制疾病，他们在提供持久的缓解方面不足，主要归因于这些药物的细胞抑制性质。即使这些药物的组合在实现持续缓解方面也是无效的。除了促进增殖和存活之外,增强的MAPK信号传导触发促凋亡应答。因此,依赖升高的MAPK信号传导的恶性肿瘤使用MAPK反馈调节因子来复杂地调节信号输出，优先考虑增殖和存活，同时抑制凋亡刺激。在这里，我们证明,在CSF3R(粒细胞集落刺激因子受体)驱动的白血病中,MAPK信号增强可上调双特异性磷酸酶1(DUSP1)的表达,从而抑制对白血病发生至关重要的凋亡刺激.因此,小鼠中Dusp1的遗传缺失赋予CSF3R诱导的白血病合成致死性。机械上,白血病环境中的DUSP1耗竭导致JNK1/2的激活，导致BIM和P53的诱导表达，同时抑制选择性触发白血病细胞凋亡反应的BCL2表达。由于由DUSP6的脱靶抑制引起的ERK1/2反弹,单独的BCI(DUSP1抑制剂)对DUSP1的药理学抑制缺乏抗白血病活性。因此,在临床前小鼠模型中,BCI与MEK抑制剂联合成功治愈CSF3R诱导的白血病.我们的发现强调了DUSP1在由增强的MAPK信号驱动的白血病转化中的关键作用，并倡导开发选择性DUSP1抑制剂用于治愈性治疗结果。
