RIP1/RIP3-Calpain-Stat3 and NF-kappa B pathways in AML pathogenesis and treatment

RIP1/RIP3-Calpain-Stat3 和 NF-kappa B 通路在 AML 发病机制和治疗中的作用

基本信息

批准号：
10401827
负责人：
Jiwang Zhang
金额：
$ 33.27万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401827
关键词：
Acute Myelocytic Leukemia Alternative Splicing Animal Model Apoptosis Attenuated Bortezomib C-terminal Calpain Cells Chemicals Clinical Dominant-Negative Mutation Drug resistance Electron Transport Family Gene Expression Genetic Transcription Growth Half-Life Hematopoietic stem cells Human Inflammatory Interleukin-1 Receptors Interleukin-1 beta Leukemic Cell MLL gene Malignant Neoplasms Mediating Mitochondria Molecular Mutation NF-kappa B NPM1 gene Necrosis Normal tissue morphology Pathogenesis Pathway interactions Patients Peptide Hydrolases Phosphotransferases Play Production Prognosis Proteasome Inhibitor Protein Isoforms Protein Kinase Protein-Serine-Threonine Kinases Proteins RIPK1 gene RIPK3 gene RNA Splicing Receptor Activation Receptor Inhibition Reporter Reporting Repression Role Signal Pathway Signal Transduction Stat3 Signaling Pathway TNF gene Testing Time Transactivation Treatment Protocols Xenograft Model Xenograft procedure acute myeloid leukemia cell cancer therapy chemotherapy cytokine dosage improved in vivo inhibitor leukemia leukemia treatment leukemic stem cell member novel self-renewal targeted treatment transcription factor tumor tumor growth tumorigenesis

项目摘要

Both NF-κB and Stat3 are abnormally activated in leukemic blasts and are implicated in drug-resistance and poor prognosis, suggesting they could be potential targets for therapy. We found that inactivation of both NF-κB and Stat3 signaling pathways synergistically represses self-renewal and drug-resistance in leukemia stem cells (LSCs), suggesting a compensatory role for these two pathways in the pathogenesis of leukemia. Stat3α and Stat3β are two major splicing isoforms. Active Stat3α promotes tumor growth by regulating target gene expression (functions as a transcription factor) and controlling mitochondrial production of ATP and ROS (functions as a regulator of the electron transport chain), while Stat3β lacks a transactivation domain and functions as a dominant-negative to Stat3α. All currently used inhibitors of Stat3 only repress its transcriptional activity without taking consideration of its mitochondrial activity, which might explain why these inhibitors failed to repress leukemia in patients. It was reported that induction of the switch from Stat3α to Stat3β provides a better tumor repressive effect than inhibition of both isoforms. We found that we can induce such a switch by inhibiting the serine/threonine-protein kinases receptor-interacting protein kinase 1 (Rip1) and Rip3. Rip3 and NF-κB are parallel downstream signaling pathways of Rip1, mediating cytokine-induced kinase- dependent and -independent activities of Rip1. We found that a moderate level of activation of Rip1-Rip3 kinase signaling exists in acute myeloid leukemia (AML) cells with MLL1-rearrangement (MLL-r) or NPM1 mutation (NPM1c+). Rip1-Rip3 signaling plays distinct roles in normal hematopoietic stem/progenitor cells（HSPCs）and AML cells. In HSPCs, Rip1-Rip3 signaling mediates TNFα and IL1β-induced necroptosis, while in AML cells, the moderate activation of such signaling is required for maintaining the levels of Stat3α by inhibition of calpain (CAPN), a family of proteolytic enzymes. CAPN reduces Stat3α and enhances Stat3β by specifically cleaving Stat3α protein and also SFRS5, a splice regulator for alternative splicing for Stat3α. Inhibition of Rip1-Rip3 kinase signaling results in depletion of Stat3α and an increase of Stat3β. Our study suggested that, as with co-inhibition of Stat3 and NF-κB, co-inhibition of Rip1-Rip3 signaling and NF-κB also compromises self-renewal of LSCs and sensitizes AML to standard chemotherapy. We want to test our novel combination treatment regimen in primary human AML cells using xenograft models. We also intend to elucidate the molecular mechanisms by which Stat3 and NF-κB regulate self-renewal and drug-resistance in LSCs as well as the molecular mechanism by which Rip3 signaling regulates CAPN-dependent Stat3 isoform switch. The expected results of this study will allow us to determine whether combinations of currently known inhibitors of Rip1/Rip3 and NF-kB signaling could improve treatment for MLL-r and NPM1c+ AML when combined with standard chemotherapy. The mechanistic studies will provide detailed information allowing us to more effectively target the Rip3-CAPN-Stat3 pathway to treat AML.

NF-κB 和 Stat3 在白血病原始细胞中均异常激活，并与耐药性有关和不良预后，他们认为这可能是治疗的潜在目标。 NF-κB 和 Stat3 信号通路协同抑制白血病干细胞的自我更新和耐药性细胞（LSC），表明这两条途径在白血病的发病机制中具有代偿作用。 Stat3α 和 Stat3β 是两种主要的剪接亚型，活性 Stat3α 通过调节促进肿瘤生长。靶基因表达（作为转录因子）并控制线粒体 ATP 和 ROS（作为电子传递链的调节器），而 Stat3β 缺乏反式激活结构域，目前使用的所有 Stat3 抑制剂仅抑制其转录。活性而不考虑其线粒体活性，这可能解释了为什么这些抑制剂失败据报道，诱导从 Stat3α 转换为 Stat3β 可以抑制患者的白血病。我们发现我们可以通过诱导这种转换来实现比抑制两种亚型更好的肿瘤抑制效果。抑制丝氨酸/苏氨酸蛋白激酶受体相互作用蛋白激酶 1 (Rip1) 和 Rip3。 Rip3 和 NF-κB 是 Rip1 的平行下游信号通路，介导细胞因子诱导的激酶我们发现 Rip1-Rip3 激酶具有中等水平的激活。信号传导存在于具有 MLL1 重排 (MLL-r) 或 NPM1 突变的急性髓系白血病 (AML) 细胞中 (NPM1c+)。Rip1-Rip3 信号在正常造血干/祖细胞 (HSPC) 和在 HSPC 中，Rip1-Rip3 信号介导 TNFα 和 IL1β 诱导的坏死性凋亡，而在 AML 细胞中，通过抑制钙蛋白酶来维持 Stat3α 水平需要适度激活此类信号传导 (CAPN) 是一个蛋白水解酶家族，通过特异性裂解减少 Stat3α 并增强 Stat3β。 Stat3α 蛋白以及 SFRS5，一种用于抑制 Stat3α 选择性剪接的剪接调节因子。我们的研究表明，与共抑制一样，信号传导会导致 Stat3α 的消耗和 Stat3β 的增加。 Stat3 和 NF-κB 的共同抑制，同时抑制 Rip1-Rip3 信号和 NF-κB 也会损害 LSC 的自我更新，使 AML 对标准化疗敏感，我们希望在初级治疗中测试我们的新型联合治疗方案。我们还打算利用异种移植模型来阐明 Stat3 的分子机制。 NF-κB调节LSC自我更新和耐药性及其分子机制 Rip3 信号传导调节 CAPN 依赖性 Stat3 亚型开关。这项研究的预期结果将使我们能够确定目前已知的组合是否 Rip1/Rip3 和 NF-kB 信号传导抑制剂联合使用可改善 MLL-r 和 NPM1c+ AML 的治疗机制研究将提供详细信息，使我们能够了解更多信息。有效靶向 Rip3-CAPN-Stat3 通路来治疗 AML。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In Vitro Expansion of Hematopoietic Stem Cells by Inhibition of Both GSK3 and p38 Signaling.

通过抑制 GSK3 和 p38 信号传导进行造血干细胞的体外扩增。

DOI：
发表时间：
2019
期刊：
影响因子：
4
作者：
Li, Jing;Zhang, Lei;Yin, Lizhi;Ma, Na;Wang, Tian;Wu, Yuanyuan;Wang, Ming;Yang, Xingxing;Xu, Hui;Hao, Caiqin;Li, Wenyan;Wei, Wei;Xu, Yan;Zhang, Feng;Breslin, Peter;Zhang, Jiwang;Zhang, Jun
通讯作者：
Zhang, Jun

Increasing genomic discovery in newly diagnosed multiple myeloma: defining disease biology and its correlation to risk.

增加新诊断的多发性骨髓瘤的基因组发现：定义疾病生物学及其与风险的相关性。

DOI：
发表时间：
2022-07
期刊：
影响因子：
3.5
作者：
Hagen, Patrick;Sellin, Mark;Berg, Stephanie;Zhang, Jiwang
通讯作者：
Zhang, Jiwang

High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions.

新诊断的多发性骨髓瘤的高风险疾病：超出 R-ISS 和 IMWG 的定义。

DOI：
发表时间：
2022-05-30
期刊：
影响因子：
12.8
作者：
Hagen, Patrick;Zhang, Jiwang;Barton, Kevin
通讯作者：
Barton, Kevin

Myc-Miz1 signaling promotes self-renewal of leukemia stem cells by repressing Cebpα and Cebpδ.

Myc-Miz1 信号通过抑制 Cebpα 和 Cebpδ 促进白血病干细胞的自我更新。

DOI：
发表时间：
2020-04-02
期刊：
影响因子：
20.3
作者：
Zhang, Lei;Li, Jing;Xu, Hui;Shao, Xianyu;Fu, Li;Hou, Ye;Hao, Caiqing;Li, Wenyan;Joshi, Kanak;Wei, Wei;Xu, Yan;Zhang, Feng;Dai, Shaojun;Breslin, Peter;Zhang, Jiwang;Zhang, Jun
通讯作者：
Zhang, Jun

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches.

造血干细胞及其生态位衰老的分子和细胞机制。