Neutrophil elastase-mediated proteolysis of the tumor suppressor p200 CUX1 promotes cell proliferation and inhibits cell differentiation in APL

Yu, Lihua; Liu, Zhong; Xiong, Likuan; Dan, Wenran; Li, Jian; Ye, Jiao; Wan, Peng; Luo, Xu; Chu, Xuan; Liu, Chen; He, Chong; Mu, Fenglin; Liu, Beizhong

doi:10.1016/j.lfs.2019.117229

Cited by 8 publications

(4 citation statements)

References 45 publications

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“…Immune infiltration is a feature of most cancers, and many cancers have a complex chemokine network that modulates tumor cell growth, survival and migration, as well as the extent and phenotype of this infiltration [ 26 , 27 ]. Neutrophils might play an essential role in tumor progression and development by providing a suitable microenvironment for their growth, thus serving as biomarkers for inflammation and as therapeutic targets [ 28 , 29 ]. On the other hand, tumor-associated macrophages (TAMs) promote tumor progression by providing nutrients for the invasion of tumor cells [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Development of an immune-related prognostic index associated with osteosarcoma

et al. 2020

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Tumor immunity is closely associated with the prognosis of tumors, including osteosarcoma (OS). The aim of the present study was to construct an immune-related prognostic index (PI) to predict the prognosis of OS. Herein, OS expression data were sourced from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database . We divided the OS patients into nonmetastatic and metastatic groups, allowing differentially immune-related genes (DIRGs) to be selected. After DIRGs were further investigated by enrichment analysis, four keys prognostic IRGs (CD79A, CSF3R, MTNR1B and NPPC) were identified using a Cox proportional hazards model . Then, an immune-related prognostic index was constructed. Finally, gene set enrichment analysis (GSEA) was employed to further explore the underlying mechanisms. The difference in tumor-infiltrating immune cell (TIIC) abundance was also discussed. In our study, eight upregulated genes and 30 downregulated genes were identified. Several Gene Ontology (GO) terms and the most significantly enriched KEGG pathways were immune-associated functions and pathways. Four genes, including CD79A, CSF3R, MTNR1B and NPPC, were used to establish a risk assessment model for evaluating OS prognosis. GSEA revealed that the risk score was related to cytokine receptor interaction and to the chemokine and B cell receptor signaling pathways. Furthermore, high risk markedly related to the infiltration of several immune cell types, including M2 macrophages, naïve CD4 T cells, and CD8 T cells . In sum, we developed a survival model for OS. The underlying molecular mechanisms of the high-risk group may affect immune-related biological processes and TIICs. Abbreviations TARGET : Therapeutically Applicable Research To Generate Effective Treatments; PI: Prognostic index; OS: Osteosarcoma; DIRGs: Differentially immune-related genes; GSEA: Gene set enrichment analysis; TIIC: Tumor-infiltrating immune cell.

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Section: Discussionmentioning

confidence: 99%

Development of an immune-related prognostic index associated with osteosarcoma

et al. 2020

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“…Sepsis-driven DIC involves leukocyte elastase degradation of cross-linked fibrin outside of the physiologic plasmin-driven fibrin degradation pathway [ 56 ]. Moreover, high levels of leukocyte elastase are seen in APL, likely contributing to both hyperfibrinolysis and to proteolysis of tumor suppressor p200 CUX1, leading to disease progression [ 57 , 58 ]. However, a contradictory report demonstrated low levels of elastase degraded fibrin/fibrinogen in APL, raising a question about the role of elastase in contributing to fibrinolysis in APL [ 58 ].…”

Section: Pathophysiology Of Hemorrhage In Aplmentioning

confidence: 99%

“…Moreover, high levels of leukocyte elastase are seen in APL, likely contributing to both hyperfibrinolysis and to proteolysis of tumor suppressor p200 CUX1, leading to disease progression [ 57 , 58 ]. However, a contradictory report demonstrated low levels of elastase degraded fibrin/fibrinogen in APL, raising a question about the role of elastase in contributing to fibrinolysis in APL [ 58 ]. A similar proteolytic mechanism involving matrix metalloproteases 2 and 9 (MMP2 and MMP9, respectively) has also been suggested.…”

Section: Pathophysiology Of Hemorrhage In Aplmentioning

confidence: 99%

The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management

Hermsen

Hambley

2023

Cancers

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Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are due, in part, to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two targeted and highly active agents in this disease. However, there remains a considerable morbidity and mortality risk in APL secondary to clinically significant hemorrhagic and/or thrombotic events. Prevention and treatment of these coagulopathic complications remain significant impediments to further progress in optimizing outcomes for patients with APL. Moreover, the relative rarity of APL hinders adequately powered randomized controlled trials for evaluating APL coagulopathy management strategies. This review draws from peer-reviewed works falling between initial descriptions of APL in 1957 and work published prior to January 2023 and provides an updated overview of the pathophysiology of hemorrhagic and thrombotic complications in APL, outlines risk stratification parameters, and compiles current clinical best practices. An improved understanding of the pathophysiologic mechanisms driving hemorrhage and thrombosis along with the completion of well-designed trials of management strategies will assist clinicians in developing interventions that mitigate these devastating complications in an otherwise largely curable disease.

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“…In addition to the annexin II-plasmin axis, other pathways triggered by presence of abnormal myeloid cells could set the stage for the dramatic drop in fibrinogen seen in APL. Abnormal elastase activity and activation of matrix metallopeptidases may contribute to the initial bleeding risk of patients with APL, though more research is needed to define their role (28)(29)(30)(31). In addition, a number of investigators have reported increased levels of tissue factor pathway inhibitor (TFPI) in patients with APL.…”

Section: Mechanisms Of Hemorrhage In Aplmentioning

confidence: 99%

Coagulopathy in Acute Promyelocytic Leukemia: Can We Go Beyond Supportive Care?

2021

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Acute promyelocytic leukemia (APL) is characterized by frequent complications due to a distinct coagulopathy. While advances in treatments have improved long-term survival, hemorrhagic and thrombotic complications remain the most common causes of death and morbidity. Improved understanding of the mechanisms of the coagulopathy associated with APL may lead to therapeutic interventions to mitigate the risk of hemorrhage and thrombosis.

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Neutrophil elastase-mediated proteolysis of the tumor suppressor p200 CUX1 promotes cell proliferation and inhibits cell differentiation in APL

Cited by 8 publications

References 45 publications

Development of an immune-related prognostic index associated with osteosarcoma

Development of an immune-related prognostic index associated with osteosarcoma

The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management

Coagulopathy in Acute Promyelocytic Leukemia: Can We Go Beyond Supportive Care?

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