Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

Goyama, Susumu; Shrestha, Mahesh; Schibler, Janet; Rosenfeldt, Leah; Miller, Wendy R.; O’Brien, Eric; Mizukawa, Benjamin; Kitamura, Toshio; Palumbo, Joseph S.; Mulloy, James C.

doi:10.1038/onc.2016.416

Cited by 22 publications

(17 citation statements)

References 45 publications

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“…To generate RUNX1-ETO9a leukemia in vivo, E14.5 c-kit + fetal liver cells derived from C57BL/6 (Ly5.2) mice were transduced with RUNX1-ETO9a together with the combinations of ASXL1-MT, ASXL1-MT-K351R and BAP1, and were transplanted into sublethally irradiated 8- to 12-week-old female C57/B6J (Ly5.1) mice (Sankyo Labo Service Corporation, Tokyo, Japan) 53 . cSAM cells and MLL-AF9 cells were generated by transducing ASXL1-MT and SETBP1-D868N or MLL-AF9 into murine bone marrow progenitors, respectively 19 , 54 . In some experiments, these cells were transduced with Cas9 and Bap1-targeting sgRNAs, and were transplanted into sublethally irradiated 8- to 12-week-old female C57/B6J (Ly5.1) mice.…”

Section: Methodsmentioning

confidence: 99%

“…For UBE2O expression, we used pLV-Myc-UBE2O WT and pLV-Myc-UBE2O C885S [gifts from Dr. Dijke 60 ]. For RUNX1-ETO expression, we used HA-tagged RUNX1-ETO or RUNX1-ETO9a in a pMSCV-IRES-Thy1.1 retroviral vector 54 . For MLL-AF9 expression, we used pMSCV-MLL-AF9-pgk-EGFP retroviral vector 54 .…”

Section: Methodsmentioning

confidence: 99%

“…For RUNX1-ETO expression, we used HA-tagged RUNX1-ETO or RUNX1-ETO9a in a pMSCV-IRES-Thy1.1 retroviral vector 54 . For MLL-AF9 expression, we used pMSCV-MLL-AF9-pgk-EGFP retroviral vector 54 . For HOXA7 and HOXA9 expression, we used Flag-tagged HOXA7 and HOXA9 in pMSCV-neo retroviral vector.…”

Section: Methodsmentioning

confidence: 99%

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Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

et al. 2018

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ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

et al. 2018

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“…Thrombin-induced PAR-1 activation breaks down extracellular matrix and basement membrane to increase MMP-1/-9 levels, which is closely related to nasopharyngeal carcinoma metastasis [ 106 ]. PAR-1 enhances acute myeloid leukemia leukemia stem cell activity and aggravates disease progression [ 108 – 109 ]. The expression of PAR-1 in esophageal squamous cell carcinoma was increased [ 110 ], to promote glioma cell malignancy and glioblastoma neoangiogenesis [ 111 ].…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer

Liu

Song

et al. 2017

Oncotarget

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PAR-1 is expressed not only in epithelium, neurons, astrocytes, immune cells, but also in cancer-associated fibroblasts, ECs (epithelial cells), myocytes of blood vessels, mast cells, and macrophages in tumor microenvironment, whereas PAR-1 stimulates macrophages to synthesize and secrete thrombin as well as other growth factors, resulting in enhanced cell proliferation, tumor growth and metastasis. Therefore, considerable effort has been devoted to the development of inhibitors targeting PAR-1. Here, we provide a comprehensive review of PAR-1’s role in cancer invasiveness and dissemination, as well as potential therapeutic strategies targeting PAR-1 signaling.

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“…Deficiency of the PAR1 receptor on the surface of acute myeloid cells causes impaired interaction between leukaemic cells and the surrounding niche. Therefore, activation of the PAR1 receptor could also support the development of leukaemic stem cells [20]. The ability of MMP1 to activate the PAR1 receptor significantly impacts the development of acute myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

Decreased MMP1 gene expression in acute myeloid leukaemia

et al. 2019

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Acute myeloid leukaemia (AML) is a heterogeneous disorder of haematopoietic stem cells or progenitor cells. Metalloproteinases (MMPs) are proteolytic enzymes whose activity is increased in different types of solid tumours. These enzymes regulate many processes associated with tumour progression. In haematological malignancy, the role of MMPs seems to be underestimated, and only metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) have been widely examined so far. In this work, differences in metalloproteinase 1 (MMP1) gene expression between patients with AML and healthy individuals were assessed. The relative expression level of the MMP1 gene was obtained by a real time PCR method preceded by reverse transcription. The relative level of MMP1 gene expression in patients with AML was decreased when compared to that of the control group. The role of MMP1 in AML could be different from that in solid tumours. Decreased MMP1 gene expression in AML similar to that of MMP9, shows a greater role for MMP1 in normal haematopoiesis than in the development of leukaemic cells.

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Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

Cited by 22 publications

References 45 publications

Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer

Decreased MMP1 gene expression in acute myeloid leukaemia

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