Pub Date : 2023-01-16DOI: 10.3389/frhem.2022.1062705
Bing Chen, Haochuan Liu, Zhengang Liu, Fan Yang
Humanized mouse models with functional human genes, cells, and tissues are typically used for in vivo studies of diseases. Decades of studies on humanized mouse models have improved our understanding of hematopoiesis, infectious diseases, cancer biology, innate and adaptive immunity, and regenerative medicine. This review discusses the establishment and development of humanized mouse models and how they are used to model red blood cell-related diseases facilitating research in several biomedical disciplines. Furthermore, we provide approaches to overcome the limitations of these models.
{"title":"Benefits and limitations of humanized mouse models for human red blood cell-related disease research","authors":"Bing Chen, Haochuan Liu, Zhengang Liu, Fan Yang","doi":"10.3389/frhem.2022.1062705","DOIUrl":"https://doi.org/10.3389/frhem.2022.1062705","url":null,"abstract":"Humanized mouse models with functional human genes, cells, and tissues are typically used for in vivo studies of diseases. Decades of studies on humanized mouse models have improved our understanding of hematopoiesis, infectious diseases, cancer biology, innate and adaptive immunity, and regenerative medicine. This review discusses the establishment and development of humanized mouse models and how they are used to model red blood cell-related diseases facilitating research in several biomedical disciplines. Furthermore, we provide approaches to overcome the limitations of these models.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128154513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-04DOI: 10.3389/frhem.2022.1085952
Mihaiescu Dan, Bianca-Ioana Gutu, E. Severin, Vlad Tanase
Beta-thalassemia is a well-known blood genetic disorder inherited in an autosomal recessive manner. Beta-thalassemia is found everywhere in the world as a rare, relatively rare, or common disease depending on the ethnic population. Affected individuals have chronic anemia associated with delayed growth, pale skin, weakness, fatigue, and more serious complications resulting in early death. Those with the severe form need frequent lifelong transfusions and depend on blood donations to survive. This literature mini-review highlights the healthcare needs that are not optimally met by people living with beta-thalassemia. The needs-led research can help to improve clinical outcomes through more appropriate management of the disease, increase provider satisfaction, and reduce the cost of care.
{"title":"Innovative and Needs-led research on β-thalassemia treatment methods","authors":"Mihaiescu Dan, Bianca-Ioana Gutu, E. Severin, Vlad Tanase","doi":"10.3389/frhem.2022.1085952","DOIUrl":"https://doi.org/10.3389/frhem.2022.1085952","url":null,"abstract":"Beta-thalassemia is a well-known blood genetic disorder inherited in an autosomal recessive manner. Beta-thalassemia is found everywhere in the world as a rare, relatively rare, or common disease depending on the ethnic population. Affected individuals have chronic anemia associated with delayed growth, pale skin, weakness, fatigue, and more serious complications resulting in early death. Those with the severe form need frequent lifelong transfusions and depend on blood donations to survive. This literature mini-review highlights the healthcare needs that are not optimally met by people living with beta-thalassemia. The needs-led research can help to improve clinical outcomes through more appropriate management of the disease, increase provider satisfaction, and reduce the cost of care.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"224 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133301122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-09-14DOI: 10.3389/frhem.2023.1235170
Yaseswini Neelamraju, Evisa Gjini, Sagar Chhangawala, Hao Fan, Shuning He, Chang-Bin Jing, Ashley T Nguyen, Subhash Prajapati, Caroline Sheridan, Yariv Houvras, Ari Melnick, A Thomas Look, Francine E Garrett-Bakelman
Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (tet2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age.
Methods: In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs).
Results and discussion: A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in tet2m/m HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of tet2-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.
{"title":"Depletion of <i>tet2</i> results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome.","authors":"Yaseswini Neelamraju, Evisa Gjini, Sagar Chhangawala, Hao Fan, Shuning He, Chang-Bin Jing, Ashley T Nguyen, Subhash Prajapati, Caroline Sheridan, Yariv Houvras, Ari Melnick, A Thomas Look, Francine E Garrett-Bakelman","doi":"10.3389/frhem.2023.1235170","DOIUrl":"10.3389/frhem.2023.1235170","url":null,"abstract":"<p><strong>Introduction: </strong>Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (<i>tet</i>2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the <i>tet2</i> gene. The <i>tet2</i><sup><i>m/m</i></sup>-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age.</p><p><strong>Methods: </strong>In the current study, we collected progenitor cells from the kidney marrows of the adult <i>tet2</i><sup><i>m/m</i></sup> and <i>tet2</i><sup><i>wt/wt</i></sup> fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs).</p><p><strong>Results and discussion: </strong>A global increase in DNA methylation of gene promoter regions and CpG islands was observed in <i>tet2</i><sup><i>m/m</i></sup> HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in <i>tet2</i><sup><i>m/m</i></sup> HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in <i>tet2</i><sup><i>m/m</i></sup> HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of <i>tet2</i>-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with <i>tet2</i> loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.</p>","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71490973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-19DOI: 10.3389/frhem.2022.1039821
S. Hlaing, Christine J. Kurian, J. Tan, E. Behling, A. Hussein
Hemophagocytic lymphohistiocytosis (HLH) is a highly detrimental syndrome that can progress to multiorgan failure, necessitating the resources of an intensive care unit, with a mortality rate as high as 40%. Secondary HLH is usually triggered by infection, most often from a viral infection or malignancy. Management of HLH in adults is challenging as treatment algorithms targeting hyperinflammation are based on pediatric protocols, such as HLH-94 and HLH-2004. To our knowledge, there are only a few reported cases of HLH secondary to ehrlichiosis infection and none in elderly patients with multiple comorbidities. Here, we present a unique case of HLH secondary to ehrlichiosis infection in an 82-year-old female successfully treated with antibiotics and steroids.
{"title":"Case Report: A unique case of secondary hemophagocytic lymphohistiocytosis from ehrlichiosis infection","authors":"S. Hlaing, Christine J. Kurian, J. Tan, E. Behling, A. Hussein","doi":"10.3389/frhem.2022.1039821","DOIUrl":"https://doi.org/10.3389/frhem.2022.1039821","url":null,"abstract":"Hemophagocytic lymphohistiocytosis (HLH) is a highly detrimental syndrome that can progress to multiorgan failure, necessitating the resources of an intensive care unit, with a mortality rate as high as 40%. Secondary HLH is usually triggered by infection, most often from a viral infection or malignancy. Management of HLH in adults is challenging as treatment algorithms targeting hyperinflammation are based on pediatric protocols, such as HLH-94 and HLH-2004. To our knowledge, there are only a few reported cases of HLH secondary to ehrlichiosis infection and none in elderly patients with multiple comorbidities. Here, we present a unique case of HLH secondary to ehrlichiosis infection in an 82-year-old female successfully treated with antibiotics and steroids.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123533033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-15DOI: 10.3389/frhem.2022.1060029
M. Mahmoud, L. Al Mahmasani, M. Charafeddine, A. Zahreddine, N. Moukalled, J. El Cheikh, A. Bazarbachi, I. Abou Dalle
Purpose Numerous factors may affect the survival outcomes of patients with acute myeloid leukemia (AML), mainly disease-related and treatment-related factors. The impact of other factors, such as the insurance status and the distance to healthcare facilities, are still unclear and may differ between different healthcare systems. We investigated the effects of insurance status and distance to the treatment center on the survival of AML patients. Materials and methods This is a single-center, observational, retrospective study of patients diagnosed with AML (2015–2020) and treated at the American University of Beirut Medical Center in Lebanon. Data regarding patient baseline characteristics, disease-related factors, insurance status, and area of residence were collected. Multivariate Cox regression analysis was used to identify main independent predictors of overall survival (OS). Results We identified 142 AML patients with a median age of 52 years (range 18–86). Of them, 91 (64%) were males, 77 (54%) had ELN intermediate risk, and 88 (62%) patients received intensive chemotherapy. After a median follow-up of 22.4 months, the median RFS and OS were 37.4 months and not reached, respectively. A Cox regression model for OS was done using the following variables: age, gender, body mass index, comorbidities, smoking status, insurance status, distance from the center, ELN classification, treatment used, and allotransplant. A higher risk of death was seen among the uninsured patients and those living beyond 40 km from the treatment center compared with fully insured patients and those living in proximity to the center (hazard ratio [HR]: 3.65; 95% CI [1.79, 7.45], p-value <0.0001; HR: 4.38; 95% CI [1.75, 10.95], p-value 0.002, respectively). Conclusions The outcome of patients with AML does not depend only on disease-related factors, as the insurance status and the distance from the area of residence to the treatment center were found to be independent predictors of survival in AML patients.
影响急性髓系白血病(AML)患者生存结局的因素很多，主要是疾病相关因素和治疗相关因素。其他因素的影响，如保险状况和与医疗机构的距离，仍然不清楚，并且在不同的医疗保健系统之间可能有所不同。我们调查了保险状况和到治疗中心的距离对AML患者生存的影响。材料与方法本研究是一项单中心、观察性、回顾性研究，研究对象为在黎巴嫩贝鲁特美国大学医学中心接受治疗的AML患者(2015-2020)。收集有关患者基线特征、疾病相关因素、保险状况和居住地区的数据。采用多变量Cox回归分析确定总生存期(OS)的主要独立预测因子。结果142例AML患者，中位年龄52岁(范围18-86岁)。其中男性91例(64%)，ELN中度风险77例(54%)，88例(62%)接受强化化疗。中位随访22.4个月后，中位RFS和OS分别为37.4个月和未达到。采用以下变量:年龄、性别、体重指数、合并症、吸烟状况、保险状况、离中心距离、ELN分类、使用的治疗方法和同种异体移植，建立OS的Cox回归模型。无保险患者和居住在距离治疗中心40公里以外的患者的死亡风险高于完全保险患者和居住在中心附近的患者(风险比[HR]: 3.65;95% CI [1.79, 7.45]， p值<0.0001;人力资源:4.38;95% CI [1.75, 10.95]， p值分别为0.002)。结论AML患者的预后不仅仅取决于疾病相关因素，保险状况和居住地到治疗中心的距离是AML患者生存的独立预测因素。
{"title":"Impact of insurance status and distance from residence to treatment center on the outcomes of patients diagnosed with acute myeloid leukemia","authors":"M. Mahmoud, L. Al Mahmasani, M. Charafeddine, A. Zahreddine, N. Moukalled, J. El Cheikh, A. Bazarbachi, I. Abou Dalle","doi":"10.3389/frhem.2022.1060029","DOIUrl":"https://doi.org/10.3389/frhem.2022.1060029","url":null,"abstract":"Purpose Numerous factors may affect the survival outcomes of patients with acute myeloid leukemia (AML), mainly disease-related and treatment-related factors. The impact of other factors, such as the insurance status and the distance to healthcare facilities, are still unclear and may differ between different healthcare systems. We investigated the effects of insurance status and distance to the treatment center on the survival of AML patients. Materials and methods This is a single-center, observational, retrospective study of patients diagnosed with AML (2015–2020) and treated at the American University of Beirut Medical Center in Lebanon. Data regarding patient baseline characteristics, disease-related factors, insurance status, and area of residence were collected. Multivariate Cox regression analysis was used to identify main independent predictors of overall survival (OS). Results We identified 142 AML patients with a median age of 52 years (range 18–86). Of them, 91 (64%) were males, 77 (54%) had ELN intermediate risk, and 88 (62%) patients received intensive chemotherapy. After a median follow-up of 22.4 months, the median RFS and OS were 37.4 months and not reached, respectively. A Cox regression model for OS was done using the following variables: age, gender, body mass index, comorbidities, smoking status, insurance status, distance from the center, ELN classification, treatment used, and allotransplant. A higher risk of death was seen among the uninsured patients and those living beyond 40 km from the treatment center compared with fully insured patients and those living in proximity to the center (hazard ratio [HR]: 3.65; 95% CI [1.79, 7.45], p-value <0.0001; HR: 4.38; 95% CI [1.75, 10.95], p-value 0.002, respectively). Conclusions The outcome of patients with AML does not depend only on disease-related factors, as the insurance status and the distance from the area of residence to the treatment center were found to be independent predictors of survival in AML patients.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"45 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115012230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-14DOI: 10.3389/frhem.2022.967156
Shan He, X. Mao, Zhaoting Cheng, Xiaojian Zhu, M. Xiao, J. Zhou
Relapsed/refractory (R/R) mantle cell lymphoma (MCL) with primary drug resistance to Bruton tyrosine kinase inhibitor and mutated TP53 responds poorly to conventional treatments. Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most effective treatments for R/R B cell lymphoma. However, no reports of CD5 CAR T cell treatment for MCL have been reported. In this paper, we report a R/R MCL patient with primary drug resistance to BTK inhibitors and TP53 mutation enrolled in a human CD5 CAR T cell trial. Remission of the primary disease was observed half a month after CAR T cell infusion. However, ascites was observed 2 weeks later. Flow cytometry suggested disease progression and immunophenotypic transformation. CD5 in CAR T cells turned negative and the expression of CD38 was enhanced. The patient was treated with a combination of daratumumab and Gemox (gemcitabine + oxaliplatin), abdominal distension and pain were markedly reduced, and ascites disappeared. We report the first case of human CD5 CAR T cell treatment for a patient with R/R MCL, providing insight on treatment strategies for such patients.
复发/难治性(R/R)套细胞淋巴瘤(MCL)对布鲁顿酪氨酸激酶抑制剂和突变TP53的原发性耐药对常规治疗反应不佳。嵌合抗原受体(CAR) T细胞疗法已成为R/R B细胞淋巴瘤最有效的治疗方法之一。然而，目前还没有关于CD5 CAR - T细胞治疗MCL的报道。在这篇论文中，我们报道了一名原发性BTK抑制剂耐药和TP53突变的R/R MCL患者参加了一项人类CD5 CAR - T细胞试验。CAR - T细胞输注后半个月观察原发疾病的缓解。2周后出现腹水。流式细胞术提示疾病进展和免疫表型转化。CAR - T细胞中CD5转为阴性，CD38表达增强。患者经达拉单抗联合Gemox(吉西他滨+奥沙利铂)治疗，腹胀、疼痛明显减轻，腹水消失。我们报告了首例人类CD5 CAR - T细胞治疗R/R MCL患者的病例，为此类患者的治疗策略提供了见解。
{"title":"Immunophenotypic transformation in relapsed/refractory mantle cell lymphoma treated with human anti-CD5 chimeric antigen receptor T cells: A Case Report","authors":"Shan He, X. Mao, Zhaoting Cheng, Xiaojian Zhu, M. Xiao, J. Zhou","doi":"10.3389/frhem.2022.967156","DOIUrl":"https://doi.org/10.3389/frhem.2022.967156","url":null,"abstract":"Relapsed/refractory (R/R) mantle cell lymphoma (MCL) with primary drug resistance to Bruton tyrosine kinase inhibitor and mutated TP53 responds poorly to conventional treatments. Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most effective treatments for R/R B cell lymphoma. However, no reports of CD5 CAR T cell treatment for MCL have been reported. In this paper, we report a R/R MCL patient with primary drug resistance to BTK inhibitors and TP53 mutation enrolled in a human CD5 CAR T cell trial. Remission of the primary disease was observed half a month after CAR T cell infusion. However, ascites was observed 2 weeks later. Flow cytometry suggested disease progression and immunophenotypic transformation. CD5 in CAR T cells turned negative and the expression of CD38 was enhanced. The patient was treated with a combination of daratumumab and Gemox (gemcitabine + oxaliplatin), abdominal distension and pain were markedly reduced, and ascites disappeared. We report the first case of human CD5 CAR T cell treatment for a patient with R/R MCL, providing insight on treatment strategies for such patients.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"92 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114711268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-03DOI: 10.3389/frhem.2022.1020852
Susu Duan, Yifan Dang, Gaurav Manohar Rajani, K. Kis‐Tóth, Joe Salas
Efmoroctocog alfa, a recombinant factor VIII Fc fusion protein referred to herein as rFVIIIFc, is an extended half-life factor replacement therapy approved for use in patients with hemophilia A. Previous studies have shown that rFVIIIFc has an immunoregulatory effect on monocyte-derived macrophages. This study provides novel findings and an understanding of how rFVIIIFc modulates monocyte differentiation into osteoclasts. rFVIIIFc was found to engage with Fc-gamma receptors (FcγR) on the monocyte surface, leading to increased inhibitory FcγR signaling in cells. Monocyte differentiation into osteoclasts in vitro was inhibited in a concentration-dependent manner following rFVIIIFc treatment, with the interaction between the Fc domain of rFVIIIFc and FcγRII on monocytes playing a role in this effect. The C1 and C2 domains of rFVIIIFc were also found to play a role in inhibiting osteoclast formation. rFVIIIFc treatment of monocytes skewed their differentiation from osteoclasts into a group of less differentiated monocytes with unique myeloid cell phenotypes. The results of this study suggest that rFVIIIFc has a unique immune-regulatory effect on monocyte differentiation, inhibiting osteoclast formation. We propose a “double touchpoint” model for rFVIIIFc interaction with monocytes, with both the Fc domain and domains of FVIII binding to the monocyte surface. Further study is needed to determine if this immune-regulatory effect has any potential benefit on the bone and joint health of patients with hemophilia A receiving rFVIIIFc.
{"title":"Recombinant factor VIII Fc fusion protein engages monocytes via Fc and FVIII domains to reduce monocyte differentiation into osteoclasts","authors":"Susu Duan, Yifan Dang, Gaurav Manohar Rajani, K. Kis‐Tóth, Joe Salas","doi":"10.3389/frhem.2022.1020852","DOIUrl":"https://doi.org/10.3389/frhem.2022.1020852","url":null,"abstract":"Efmoroctocog alfa, a recombinant factor VIII Fc fusion protein referred to herein as rFVIIIFc, is an extended half-life factor replacement therapy approved for use in patients with hemophilia A. Previous studies have shown that rFVIIIFc has an immunoregulatory effect on monocyte-derived macrophages. This study provides novel findings and an understanding of how rFVIIIFc modulates monocyte differentiation into osteoclasts. rFVIIIFc was found to engage with Fc-gamma receptors (FcγR) on the monocyte surface, leading to increased inhibitory FcγR signaling in cells. Monocyte differentiation into osteoclasts in vitro was inhibited in a concentration-dependent manner following rFVIIIFc treatment, with the interaction between the Fc domain of rFVIIIFc and FcγRII on monocytes playing a role in this effect. The C1 and C2 domains of rFVIIIFc were also found to play a role in inhibiting osteoclast formation. rFVIIIFc treatment of monocytes skewed their differentiation from osteoclasts into a group of less differentiated monocytes with unique myeloid cell phenotypes. The results of this study suggest that rFVIIIFc has a unique immune-regulatory effect on monocyte differentiation, inhibiting osteoclast formation. We propose a “double touchpoint” model for rFVIIIFc interaction with monocytes, with both the Fc domain and domains of FVIII binding to the monocyte surface. Further study is needed to determine if this immune-regulatory effect has any potential benefit on the bone and joint health of patients with hemophilia A receiving rFVIIIFc.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127830947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-26DOI: 10.3389/frhem.2022.1005666
M. Egyed, B. Kajtár, C. Foldesi, V. Skov, L. Kjær, H. Hasselbalch
The JAK2V617F mutation is an acquired somatic mutation, which is prevalent in patients with the Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs). In these diseases the mutation gives rise to constitutive JAK-STAT signaling with increased blood cell counts and in vivo activation of neutrophils and platelets as well, which altogether contribute to a chronic inflammatory and thrombogenic state with a 12-fold increased risk of coronary disease. Treatment with recombinant interferon-alpha2 (rIFN) reduces the JAK2V617F allelic burden in a large number of MPN-patients. Long-term treatment with rIFN associates with low-burden JAK2V617F in a subset of patients and a decreased thrombosis risk as well. In the general population the JAK2V617F mutation has been shown to associate with ischemic heart disease and thrombosis. Based upon the above observations we herein report the first patient with CHIP-JAK2V617F, in whom treatment with rIFN resolved severe angina pectoris. During a short period off rIFN the symptoms reappeared to resolve in concert with reduction of JAK2V617F allele burden, when rIFN was reinstituted. The JAK2V617F mutation may be a novel therapeutic target to prohibit the development of cardiovascular diseases using rIFN either as monotherapy or in combination with potent anti-inflammatory agents.
{"title":"Ropeginterferon-alfa2b resolves angina pectoris and reduces JAK2V617F in a patient with clonal hematopoiesis of indeterminate potential: A case report","authors":"M. Egyed, B. Kajtár, C. Foldesi, V. Skov, L. Kjær, H. Hasselbalch","doi":"10.3389/frhem.2022.1005666","DOIUrl":"https://doi.org/10.3389/frhem.2022.1005666","url":null,"abstract":"The JAK2V617F mutation is an acquired somatic mutation, which is prevalent in patients with the Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs). In these diseases the mutation gives rise to constitutive JAK-STAT signaling with increased blood cell counts and in vivo activation of neutrophils and platelets as well, which altogether contribute to a chronic inflammatory and thrombogenic state with a 12-fold increased risk of coronary disease. Treatment with recombinant interferon-alpha2 (rIFN) reduces the JAK2V617F allelic burden in a large number of MPN-patients. Long-term treatment with rIFN associates with low-burden JAK2V617F in a subset of patients and a decreased thrombosis risk as well. In the general population the JAK2V617F mutation has been shown to associate with ischemic heart disease and thrombosis. Based upon the above observations we herein report the first patient with CHIP-JAK2V617F, in whom treatment with rIFN resolved severe angina pectoris. During a short period off rIFN the symptoms reappeared to resolve in concert with reduction of JAK2V617F allele burden, when rIFN was reinstituted. The JAK2V617F mutation may be a novel therapeutic target to prohibit the development of cardiovascular diseases using rIFN either as monotherapy or in combination with potent anti-inflammatory agents.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"144 11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129525152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-20DOI: 10.3389/frhem.2022.1035281
Marianna Palazzo, Gaia Ciolli, S. Pilerci, I. Attucci, L. Pengue, A. Vannucchi, E. Antonioli
Multiple myeloma patients have an increased risk of infections due to both the inherent nature of the disease and ongoing treatment. We describe the case of a patient who was treated with daratumumab-lenalidomide-dexamethasone regimen for two years and developed a parvovirus B19 infection. The clinical picture, characterized by trilinear cytopenia, was initially attributed to anti-neoplastic treatment. Later on, when the patient’s condition worsened, an extensive diagnostic workup was applied and parvovirus B19 infection was detected by PCR. Due to the lack of effective antiviral drugs, the patient received IV immunoglobulins and it took 10 days to achieve a decrease in viral copies. Physicians should be aware that recent changes in the therapeutic scenario of multiple myeloma would make patients more susceptible to atypical infections in this patient setting.
{"title":"Case report: Unexpected parvovirus B19 infection in a myeloma patient treated with daratumumab","authors":"Marianna Palazzo, Gaia Ciolli, S. Pilerci, I. Attucci, L. Pengue, A. Vannucchi, E. Antonioli","doi":"10.3389/frhem.2022.1035281","DOIUrl":"https://doi.org/10.3389/frhem.2022.1035281","url":null,"abstract":"Multiple myeloma patients have an increased risk of infections due to both the inherent nature of the disease and ongoing treatment. We describe the case of a patient who was treated with daratumumab-lenalidomide-dexamethasone regimen for two years and developed a parvovirus B19 infection. The clinical picture, characterized by trilinear cytopenia, was initially attributed to anti-neoplastic treatment. Later on, when the patient’s condition worsened, an extensive diagnostic workup was applied and parvovirus B19 infection was detected by PCR. Due to the lack of effective antiviral drugs, the patient received IV immunoglobulins and it took 10 days to achieve a decrease in viral copies. Physicians should be aware that recent changes in the therapeutic scenario of multiple myeloma would make patients more susceptible to atypical infections in this patient setting.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"13 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127742937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-19DOI: 10.3389/frhem.2022.1004717
Morgane Canonne, Fabienne George, C. Graux
Mature B cell malignancies constitute a wide range of biologically and clinically heterogeneous hematological diseases. Despite an increasingly thorough understanding of the pathophysiology of these pathologies and significant improvements in therapies, a dismal outcome still affects a large number of patients. Therefore, further investigations into new treatment perspectives are highly needed and they depend entirely on the ex vivo culture of patient cells. Primary cells usually demand superior culture models, as they are notoriously difficult to cultivate. The literature is not devoid of approaches ranging from two- to three-dimensional systems for culturing mature malignant primary B cells. However, they display substantial protocol inter-variation. This imposes a high risk of failures, repeats, and inconsistent results, which are neither compatible with the rare value of primary cells nor the efficiency of the drug discovery process. In this review, we provide a thorough overview of the different approaches that have been implemented in the literature for the culture of mature malignant primary B cells, and we discuss associated considerations and limitations to assist researchers in determining a fit-for-purpose culture system, thereby attempting to reduce the number of trials and errors as well as associated biomaterial expenditure.
{"title":"Ex vivo culture of malignant primary B cells","authors":"Morgane Canonne, Fabienne George, C. Graux","doi":"10.3389/frhem.2022.1004717","DOIUrl":"https://doi.org/10.3389/frhem.2022.1004717","url":null,"abstract":"Mature B cell malignancies constitute a wide range of biologically and clinically heterogeneous hematological diseases. Despite an increasingly thorough understanding of the pathophysiology of these pathologies and significant improvements in therapies, a dismal outcome still affects a large number of patients. Therefore, further investigations into new treatment perspectives are highly needed and they depend entirely on the ex vivo culture of patient cells. Primary cells usually demand superior culture models, as they are notoriously difficult to cultivate. The literature is not devoid of approaches ranging from two- to three-dimensional systems for culturing mature malignant primary B cells. However, they display substantial protocol inter-variation. This imposes a high risk of failures, repeats, and inconsistent results, which are neither compatible with the rare value of primary cells nor the efficiency of the drug discovery process. In this review, we provide a thorough overview of the different approaches that have been implemented in the literature for the culture of mature malignant primary B cells, and we discuss associated considerations and limitations to assist researchers in determining a fit-for-purpose culture system, thereby attempting to reduce the number of trials and errors as well as associated biomaterial expenditure.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":"72 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124253456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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