N-Acetylcysteine As a Therapeutic for JAK2V617F Myeloproliferative Neoplasms
| العنوان: | N-Acetylcysteine As a Therapeutic for JAK2V617F Myeloproliferative Neoplasms |
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| المؤلفون: | Summer Hoang, Hew Yeng Lai, Angela G. Fleischman, Gajalakshmi Ramanathan, Laura F. Mendez Luque, Kenza Elalaoui, Stefan Brooks, Brianna M. Craver |
| المصدر: | Blood. 132:1786-1786 |
| بيانات النشر: | American Society of Hematology, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Acetylcysteine, business.industry, Immunology, Medicine, Cell Biology, Hematology, Pharmacology, business, Biochemistry, medicine.drug |
| الوصف: | Chronic inflammation is common in MPN and drives disease progression and worsens symptom burden. It has been reported that JAK2V617F hematopoietic stem and progenitor cells (HSPCs) exhibit elevated basal oxidative stress compared to wild-type cells. However, JAK2V617F HSCs have a differential response than normal HSPCs upon stimulation with pro-inflammatory cytokines or lipopolysaccharide (LPS) invivo and in vitro. Specifically, JAK2V617F HSPCs do not significantly increase reactive oxygen species, exit quiescence, or increase DNA damage following LPS exposure (Blood 2017 130:4211). Therefore, we hypothesized that oxidative stress is important for differential responses of wild-type and JAK2V617F HSCs to inflammation. To compare cell responses to oxidative stress, we treated bone marrow cells from JAK2V617F knock-in and wild-type mice ex vivo with L-buthionine-S,R-sulfoximine (BSO), which reduces glutathione levels, then measured the impact on myeloid colony formation in methylcellulose. JAK2V617F knock-in bone marrow cells are resistant to oxidative stress-induced reduction in colony formation compared to wild-type bone marrow cells. This data suggests that JAK2V617F myeloid progenitors produce less reactive oxygen species in response to BSO or that these cells are resistant to oxidative stress-induced cell death. Next, we tested the effect of the anti-oxidant n-acetylcysteine (NAC) in a JAK2V617F knock-in mouse model. All hematopoietic cells in this model express JAK2V617F, these mice develop elevated blood counts, splenomegaly, and die suddenly at approximately 2-3 months of age. Surprisingly, addition of NAC (2g/L) in the drinking water extended the lifespan of JAK2V617F-knock in mice (p There is a positive correlation between leukocytosis and thrombotic risk in MPN patients. Additionally, MPN patients and mice exhibit elevated neutrophil extracellular trap (NET) formation compared to healthy controls, which contributes to the increased thrombosis in MPN. To test the effect of antioxidants on NET formation in vitro, we treated neutrophils from MPN patients or healthy donors with phorbol myristate acetate concurrently with antioxidants (NAC or ferulic acid) and assayed the presence of extracellular DNA using a SYTOX Green nucleic acid stain. Unstimulated neutrophils from MPN patients exhibited sporadic NET formation while neutrophils from healthy donors did not. Additionally, NAC and ferulic acid reduced DNA release, which is indicative of NET formation. Taken together, these data demonstrate that JAK2V617F progenitors are resistant to oxidative stress-induced cell death. Furthermore, reduction of oxidative stress with n-acetylcysteine in vivo prevented NET-induced thrombosis in JAK2V617F knock-in mice as well as in vitro in normal and MPN neutrophils. These data provide a rationale for investigating the utility of n-acetylcysteine as a therapeutic in myeloproliferative neoplasms. Disclosures No relevant conflicts of interest to declare. |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::474db552a46ac02aa86be6ac9d6e4969 https://doi.org/10.1182/blood-2018-99-117395 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........474db552a46ac02aa86be6ac9d6e4969 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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