Blood Cells Molecules and Diseases最新文献_第4页

Immunodeficiency in children with Diamond Blackfan and Diamond Blackfan like anemia 患有钻石黑扇和钻石黑扇样贫血的儿童免疫缺陷

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2025-02-07 DOI: 10.1016/j.bcmd.2025.102911

Iman Ragab , Sara Makkeyah , Noura Hassan , Michael Botros , Lydie Da Costa , Nihal Hussien Aly

Background

Diamond-Blackfan anemia Syndrome (DBAS) is a ribosomopathy with erythroid failure. DBA-like picture occurs with non-ribosomal mutation and a normal rRNA maturation. Immunodeficiency in patients with DBAS is not adequately studied. We aimed to study the frequency of infections and immunoglobulins levels in children with DBAS.

Methods

Children and adolescents with DBAS were included. Infections were scored according to the immunodeficiency related score (IDR). Total serum immunoglobulin A (IgA), IgG and IgM were measured. Molecular studies were done to a group of patients.

Results

Thirty-four patients had a median age at diagnosis of 3.6 month-old. Fourteen (41 %) patients had an IDR score of ≥6, and 4 of them (28.6 %) had low immunoglobulin levels. Patients with IDR score > 6 had significantly lower IgG (471 versus 1057 mg/dl, p = 0,032) and serum IgA (24 versus 98.5 mg/dl, p = 0.015) than IDR < 6 group. We report mortality in 8 (23.5 %) patients, two of them were related to infection. Molecular analyses were performed in 8 probands and 17 relatives (5 families); 7 of the probands carried CECR1/ADA2 gene mutation and one patient carried a pathogenic variant in RPL36 gene.

Conclusion

We highlight the presence of underlying immunodeficiency in a group of patients with DBA and DBA-like disease.

diamond - blackfan贫血综合征（DBAS）是一种伴有红细胞功能衰竭的核糖体病。非核糖体突变和正常rRNA成熟时出现类似dba的图像。DBAS患者的免疫缺陷尚未得到充分研究。我们的目的是研究DBAS患儿的感染频率和免疫球蛋白水平。方法以儿童和青少年为研究对象。根据免疫缺陷相关评分（IDR）对感染进行评分。测定血清总免疫球蛋白A （IgA）、IgG和IgM。对一组病人进行了分子研究。结果34例患者诊断时中位年龄为3.6个月。14例（41%）患者IDR评分≥6，其中4例（28.6%）患者免疫球蛋白水平低。IDR评分患者>；6例患者IgG （471 vs 1057 mg/dl, p = 0.032）和血清IgA （24 vs 98.5 mg/dl, p = 0.015）明显低于IDR和lt；6组。我们报告了8例（23.5%）患者的死亡，其中2例与感染有关。对8名先证者和17名近亲属（5个家族）进行分子分析；7例先证者携带CECR1/ADA2基因突变，1例患者携带RPL36基因致病性变异。结论：我们强调在DBA和DBA样疾病患者中存在潜在免疫缺陷。

{"title":"Immunodeficiency in children with Diamond Blackfan and Diamond Blackfan like anemia","authors":"Iman Ragab , Sara Makkeyah , Noura Hassan , Michael Botros , Lydie Da Costa , Nihal Hussien Aly","doi":"10.1016/j.bcmd.2025.102911","DOIUrl":"10.1016/j.bcmd.2025.102911","url":null,"abstract":"<div><h3>Background</h3><div>Diamond-Blackfan anemia Syndrome (DBAS) is a ribosomopathy with erythroid failure. DBA-like picture occurs with non-ribosomal mutation and a normal rRNA maturation. Immunodeficiency in patients with DBAS is not adequately studied. We aimed to study the frequency of infections and immunoglobulins levels in children with DBAS.</div></div><div><h3>Methods</h3><div>Children and adolescents with DBAS were included. Infections were scored according to the immunodeficiency related score (IDR). Total serum immunoglobulin A (IgA), IgG and IgM were measured. Molecular studies were done to a group of patients.</div></div><div><h3>Results</h3><div>Thirty-four patients had a median age at diagnosis of 3.6 month-old. Fourteen (41 %) patients had an IDR score of ≥6, and 4 of them (28.6 %) had low immunoglobulin levels. Patients with IDR score > 6 had significantly lower IgG (471 versus 1057 mg/dl, <em>p</em> <em>=</em> 0,032) and serum IgA (24 versus 98.5 mg/dl, <em>p</em> <em>=</em> 0.015) than IDR < 6 group. We report mortality in 8 (23.5 %) patients, two of them were related to infection. Molecular analyses were performed in 8 probands and 17 relatives (5 families); 7 of the probands carried <em>CECR1/ADA2</em> gene mutation and one patient carried a pathogenic variant in <em>RPL36</em> gene.</div></div><div><h3>Conclusion</h3><div>We highlight the presence of underlying immunodeficiency in a group of patients with DBA and DBA-like disease.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"111 ","pages":"Article 102911"},"PeriodicalIF":2.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Red blood cell pyruvate kinase properties in Townes and Berkeley sickle cell disease mouse models – Of mice and men 汤斯和伯克利镰状细胞病小鼠模型中的红细胞丙酮酸激酶特性-小鼠和男性

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2025-01-16 DOI: 10.1016/j.bcmd.2025.102909

Marissa J.M. Traets , Titine J.J. Ruiter , Charles Levine , Anita W. Rijneveld , Judith J. Jans , Carsten Alt , Minke A.E. Rab , Yu-Wei Chen , Richard van Wijk , Brigitte A. van Oirschot

Pyruvate kinase (PK), a key ATP-generating enzyme in glycolysis, is a target for novel sickle cell disease (SCD) therapies. Enhancing PK activity lowers 2,3-diphosphyglycerate (2,3-DPG), increases adenosine triphosphate (ATP), and may prevent red blood cell (RBC) sickling. Townes and Berkeley SCD mouse models are commonly used for the development of novel drugs for SCD, but differ from humans in 2,3-DPG and ATP levels, which could be related to underlying differences in PK properties. This study revealed important distinctions with humans (SCD vs healthy controls), such as similar PK/hexokinase (HK) ratios between sickling and non-sickling mouse models and significantly lower PK thermostability in mice. We additionally investigated the effect of a novel RBC PK activator, compound A, on PK properties and sickling tendency in these mice in order to assess SCD mouse model suitability. Results showed that a single dose of compound A led to an increased affinity of PK for phosphoenolpyruvate, a significant increase in PK/HK ratio and a decrease of 2,3-DPG levels. Together, these results offer detailed characterization in the PK properties of two commonly used SCD mouse models, and provide insight into the mode of action of PK activator therapy in SCD mice models.

丙酮酸激酶（PK）是糖酵解过程中关键的atp生成酶，是新型镰状细胞病（SCD）治疗的靶点。增强PK活性降低2,3-二磷酸甘油酸（2,3- dpg），增加三磷酸腺苷（ATP），并可能防止红细胞（RBC）镰状细胞。Townes和Berkeley SCD小鼠模型通常用于开发用于SCD的新药，但在2,3- dpg和ATP水平上与人类不同，这可能与PK特性的潜在差异有关。该研究揭示了与人类（SCD与健康对照）的重要区别，例如镰状病和非镰状病小鼠模型之间的PK/己糖激酶（HK）比率相似，并且小鼠的PK热稳定性显著降低。我们还研究了一种新的红细胞PK激活剂化合物a对这些小鼠PK特性和镰状倾向的影响，以评估SCD小鼠模型的适用性。结果表明，单剂量化合物a可提高PK对磷酸烯醇丙酮酸酯的亲和力，显著提高PK/HK比值，降低2,3- dpg水平。总之，这些结果提供了两种常用的SCD小鼠模型的PK特性的详细特征，并提供了PK激活剂治疗在SCD小鼠模型中的作用模式的见解。

{"title":"Red blood cell pyruvate kinase properties in Townes and Berkeley sickle cell disease mouse models – Of mice and men","authors":"Marissa J.M. Traets , Titine J.J. Ruiter , Charles Levine , Anita W. Rijneveld , Judith J. Jans , Carsten Alt , Minke A.E. Rab , Yu-Wei Chen , Richard van Wijk , Brigitte A. van Oirschot","doi":"10.1016/j.bcmd.2025.102909","DOIUrl":"10.1016/j.bcmd.2025.102909","url":null,"abstract":"<div><div>Pyruvate kinase (PK), a key ATP-generating enzyme in glycolysis, is a target for novel sickle cell disease (SCD) therapies. Enhancing PK activity lowers 2,3-diphosphyglycerate (2,3-DPG), increases adenosine triphosphate (ATP), and may prevent red blood cell (RBC) sickling. Townes and Berkeley SCD mouse models are commonly used for the development of novel drugs for SCD, but differ from humans in 2,3-DPG and ATP levels, which could be related to underlying differences in PK properties. This study revealed important distinctions with humans (SCD vs healthy controls), such as similar PK/hexokinase (HK) ratios between sickling and non-sickling mouse models and significantly lower PK thermostability in mice. We additionally investigated the effect of a novel RBC PK activator, compound A, on PK properties and sickling tendency in these mice in order to assess SCD mouse model suitability. Results showed that a single dose of compound A led to an increased affinity of PK for phosphoenolpyruvate, a significant increase in PK/HK ratio and a decrease of 2,3-DPG levels. Together, these results offer detailed characterization in the PK properties of two commonly used SCD mouse models, and provide insight into the mode of action of PK activator therapy in SCD mice models.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"111 ","pages":"Article 102909"},"PeriodicalIF":2.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Short- and long-term alterations of hematopoietic cell lineages in rats with congenital iron deficiency 先天性缺铁大鼠造血细胞谱系的短期和长期改变。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-12-17 DOI: 10.1016/j.bcmd.2024.102908

Anthony Babu , Zachary R. Smith , Narmin Mukhtarova , Ashajyothi M. Siddappa , Pamela J. Kling

Data support that fetal iron delivery is prioritized to hemoglobin in erythrocytes (RBC). Iron deficiency (ID) during pregnancy can cause congenital ID, i.e., low fetal iron acquisition. Because how congenital ID impacts other fetal hematopoietic cell lineages is unknown our pilot study examined this in a rat congenital ID model. Pregnant dams fed ID diets were compared to iron sufficient (IS) controls. Iron indices, complete cell counts with differentials, and microscopic morphology were studied at birth P2–3, mid-recovery P15 and adolescent post-recovery P45. Compared to IS at birth, ID rats exhibited 350 % higher zinc protoporphyrin/heme, 70 % lower plasma ferritin, 30 % lower hemoglobin, 25 % fewer platelets, but nucleated RBC (nRBC) and reticulocytes did not differ. Compared to IS at birth, ID rats exhibited 36 % fewer white counts (WBC) but proportionate lymphocytes and granulocytes (all P < 0.015). Compared to IS at P45, RBC, platelets, and WBC numbers did not differ, but lymphocytes were relatively lower in ID (P < 0.01). Microscopic morphology differed from IS in ID, with persistent differences at P45. Because altered inflammatory programming was previously reported in congenital ID and because this pilot study found altered WBC populations, this model of congenital ID is well situated to investigate long-term developmental programming.

数据支持胎儿铁递送优先于红细胞（RBC）中的血红蛋白。怀孕期间缺铁（ID）可导致先天性ID，即低胎儿铁获取。由于先天性ID如何影响其他胎儿造血细胞系尚不清楚，我们的初步研究在大鼠先天性ID模型中对此进行了检查。饲喂低铁日粮的孕坝与铁足量（IS）对照组进行比较。对出生时P2-3、恢复中期P15和青春期恢复后P45的铁指数、全细胞计数和显微形态学进行了研究。与出生时的IS相比，ID大鼠表现出350%的锌原卟啉/血红素高，70%的血浆铁蛋白低，30%的血红蛋白低，25%的血小板少，但有核红细胞（nRBC）和网织红细胞没有差异。与出生时的IS相比，ID大鼠的白细胞计数（WBC）减少了36%，但淋巴细胞和粒细胞的比例(均为P

{"title":"Short- and long-term alterations of hematopoietic cell lineages in rats with congenital iron deficiency","authors":"Anthony Babu , Zachary R. Smith , Narmin Mukhtarova , Ashajyothi M. Siddappa , Pamela J. Kling","doi":"10.1016/j.bcmd.2024.102908","DOIUrl":"10.1016/j.bcmd.2024.102908","url":null,"abstract":"<div><div>Data support that fetal iron delivery is prioritized to hemoglobin in erythrocytes (RBC). Iron deficiency (ID) during pregnancy can cause congenital ID, i.e., low fetal iron acquisition. Because how congenital ID impacts other fetal hematopoietic cell lineages is unknown our pilot study examined this in a rat congenital ID model. Pregnant dams fed ID diets were compared to iron sufficient (IS) controls. Iron indices, complete cell counts with differentials, and microscopic morphology were studied at birth P2–3, mid-recovery P15 and adolescent post-recovery P45. Compared to IS at birth, ID rats exhibited 350 % higher zinc protoporphyrin/heme, 70 % lower plasma ferritin, 30 % lower hemoglobin, 25 % fewer platelets, but nucleated RBC (nRBC) and reticulocytes did not differ. Compared to IS at birth, ID rats exhibited 36 % fewer white counts (WBC) but proportionate lymphocytes and granulocytes (all <em>P</em> < 0.015). Compared to IS at P45, RBC, platelets, and WBC numbers did not differ, but lymphocytes were relatively lower in ID (<em>P</em> < 0.01). Microscopic morphology differed from IS in ID, with persistent differences at P45. Because altered inflammatory programming was previously reported in congenital ID and because this pilot study found altered WBC populations, this model of congenital ID is well situated to investigate long-term developmental programming.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"111 ","pages":"Article 102908"},"PeriodicalIF":2.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Clinical utility of relative telomere length analysis in pediatric bone marrow failure” [Blood Cells Mol. Dis. 109 (2024) 102882] 更正："相对端粒长度分析在小儿骨髓衰竭中的临床应用" [Blood Cells Mol. Dis. 109 (2024) 102882]。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-11-07 DOI: 10.1016/j.bcmd.2024.102899

Shilpa Amatya , Prateek Bhatia , Sudhanshi Raina , Sreejesh Sreedharanunni , Minu Singh , Emine Rahman , M.V. Archana , Amita Trehan

引用次数: 0

Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1) 明显的小红细胞症和转铁蛋白饱和度升高：考虑 SLC11A2（DMT1）的变异。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-11-02 DOI: 10.1016/j.bcmd.2024.102898

Alexandre Raynor , Katell Peoc'h , Camille Boi , Hana Manceau , Serge Pissard , Karim Diallo , Caroline Kannengiesser , Pierre Rohrlich

Congenital microcytic anemias are rare diseases associated with decreased hemoglobin synthesis and red blood cells of low corpuscular volume. DMT1/NRAMP2 is a highly conserved divalent cation transporter encoded by the SLC11A2 gene, expressed at the membrane of various cells. It ensures ferrous iron absorption from the apical membrane of enterocytes, iron recovery from urine by renal tubules, and acidified endosome uptake after transferrin internalization. Pathogenic DMT1 variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of SLC11A2 (c.469A>G, p.Ile157Val) compound with known p.Arg416Cys associated with a frankly microcytic anemia and increased transferrin saturation. The clinical picture observed in the patient was exceptionally mild, extending the field of the DMT1 phenotypes to borderline anemias.

先天性小红细胞性贫血是一种罕见的疾病，与血红蛋白合成减少和红细胞体积小有关。DMT1/NRAMP2 是一种高度保守的二价阳离子转运体，由 SLC11A2 基因编码，在各种细胞膜上表达。它能确保肠细胞顶膜吸收亚铁，肾小管从尿液中回收铁，以及转铁蛋白内化后酸化内质体的吸收。迄今为止，已在 10 个个体中描述了致病性 DMT1 变体，这些变体与隐性低色素性贫血和铁超载有关。在此，我们报告了一种新的 SLC11A2 变体（c.469A>G，p.Ile157Val）与已知的 p.Arg416Cys 复合体，该变体与坦率的小红细胞性贫血和转铁蛋白饱和度增高有关。该患者的临床症状非常轻微，将 DMT1 表型的范围扩大到了边缘性贫血。

引用次数: 0

Identification of Nfel1a and Nfel3 as novel regulators for zebrafish thrombopoiesis 鉴定 Nfel1a 和 Nfel3 作为斑马鱼血栓形成的新型调节器

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-10-10 DOI: 10.1016/j.bcmd.2024.102897

Weam Fallatah, Sanchi Dhinoja, Ayah Al Qaryoute, Jabila Mary, Vallerie Cheng, Pudur Jagadeeswaran

In mammalian hematopoiesis, megakaryocytes mature and become polyploid in the bone marrow before releasing platelets into circulation. In contrast, fish produce thrombocytes in kidney marrow, where young thrombocytes undergo maturation in circulation, akin to platelets. Despite morphological differences, our single-cell sequencing revealed significant gene expression similarities between fish thrombocytes and mammalian megakaryocytes, including Nfe2, which is crucial in platelet production. In addition to nfe2 expression, we found four nfe2-related genes, nfe2I1a, nfe2I1b, nfe2I2a, and nfe2I3, were expressed in mature thrombocytes. However, only nfe2, nfe2l2a, and nfe2l3 are expressed in young thrombocytes. Thus, we hypothesized that Nfe2-related factors may also be involved in thrombocyte production. To address this, we knocked down the four novel nfe2-related genes by the piggyback method and found both young and mature thrombocytes reduced when nfe2, nfe2l1a, and nfe2l3 were knocked down. They also exhibited greater gill bleeding and prolonged time to occlusion (TTO) compared to controls. In summary, our study shows Nfe2I1a and Nfe2l3 as novel transcription factors that are positive regulators influencing adult zebrafish thrombopoiesis.

在哺乳动物的造血过程中，巨核细胞在骨髓中成熟并变成多倍体，然后将血小板释放到血液循环中。与此相反，鱼类在肾脏骨髓中产生血小板，年轻的血小板在血液循环中成熟，类似于血小板。尽管形态上存在差异，但我们的单细胞测序发现，鱼类血小板与哺乳动物巨核细胞的基因表达有显著相似之处，其中包括对血小板生成至关重要的 Nfe2。除了 nfe2 的表达外，我们还发现四个与 nfe2 相关的基因 nfe2I1a、nfe2I1b、nfe2I2a 和 nfe2I3 也在成熟的血小板中表达。然而，只有 nfe2、nfe2l2a 和 nfe2l3 在年轻血小板中表达。因此，我们推测 Nfe2 相关因子可能也参与了血小板的生成。为了解决这个问题，我们用猪背法敲除了四个新的 nfe2 相关基因，发现当 nfe2、nfe2l1a 和 nfe2l3 被敲除后，幼年和成熟的血小板都会减少。与对照组相比，它们还表现出更大的鳃出血量和更长的闭塞时间（TTO）。总之，我们的研究表明，Nfe2I1a 和 Nfe2l3 是影响斑马鱼成体血栓形成的新型转录因子。

{"title":"Identification of Nfel1a and Nfel3 as novel regulators for zebrafish thrombopoiesis","authors":"Weam Fallatah, Sanchi Dhinoja, Ayah Al Qaryoute, Jabila Mary, Vallerie Cheng, Pudur Jagadeeswaran","doi":"10.1016/j.bcmd.2024.102897","DOIUrl":"10.1016/j.bcmd.2024.102897","url":null,"abstract":"<div><div>In mammalian hematopoiesis, megakaryocytes mature and become polyploid in the bone marrow before releasing platelets into circulation. In contrast, fish produce thrombocytes in kidney marrow, where young thrombocytes undergo maturation in circulation, akin to platelets. Despite morphological differences, our single-cell sequencing revealed significant gene expression similarities between fish thrombocytes and mammalian megakaryocytes, including Nfe2, which is crucial in platelet production. In addition to <em>nfe2</em> expression, we found four <em>nfe2-</em>related genes, <em>nfe2I1a, nfe2I1b, nfe2I2a,</em> and <em>nfe2I3,</em> were expressed in mature thrombocytes. However, only <em>nfe2, nfe2l2a,</em> and <em>nfe2l3</em> are expressed in young thrombocytes. Thus, we hypothesized that Nfe2-related factors may also be involved in thrombocyte production. To address this, we knocked down the four novel <em>nfe2-</em>related genes by the piggyback method and found both young and mature thrombocytes reduced when <em>nfe2, nfe2l1a,</em> and <em>nfe2l3</em> were knocked down. They also exhibited greater gill bleeding and prolonged time to occlusion (TTO) compared to controls. In summary, our study shows Nfe2I1a and Nfe2l3 as novel transcription factors that are positive regulators influencing adult zebrafish thrombopoiesis.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102897"},"PeriodicalIF":2.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitor use: A review of the current knowledge and future directions 与使用免疫检查点抑制剂相关的嗜血细胞淋巴组织细胞增多症：回顾当前知识和未来方向。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-09-30 DOI: 10.1016/j.bcmd.2024.102896

Charlotte S. Walmsley , Zachary Schoepflin , Charlotte De Brabandt , Deepa Rangachari , Shana Berwick , Rushad Patell

Hemophagocytic lymphohistiocytosis (HLH) is a severe and often lethal inflammatory syndrome characterized by excessive immune activation leading to fever, cytopenias, and multiorgan involvement. Immune checkpoint inhibitors (ICIs) are central to many contemporary cancer regimens, but their use is associated with immune-related adverse events. Here, we report a case of ICI-induced HLH successfully treated with single agent dexamethasone and provide a scoping review of the literature for cases of ICI-induced HLH with a focus on treatment strategies and outcomes. Using the Medline database, we searched for cases of ICI-associated HLH, with a total of 51 cases reported between 2017 and 2023. Our results underscore the severe nature of this disease, with a 13.7 % mortality rate across 51 case reports. Treatment strategies for ICI-induced HLH were variable: steroids alone (56.9 %), steroids with etoposide (17.6 %), steroids with tociluzumab (11.8 %), among other combinations. Our literature review indicates that steroids alone may be sufficient treatment in some cases of ICI-HLH, with comparable mortality with steroids alone (n = 29) (13.8 %) to that of cases treated with both steroids and immunomodulators (n = 15, 13.3 %). Moreover, all patients treated with steroids and tocilizumab survived (n = 6), suggesting that tocilizumab may be a reasonable next line of therapy when steroid monotherapy proves inadequate. We propose an outline for investigation and treatment of this rare complication of ICI use. Finally, we discuss possible future approaches to develop evidence-based strategies for the diagnosis and management of ICI-induced HLH including the importance of integrating the role of patient community involvement.

嗜血细胞淋巴组织细胞增多症（HLH）是一种严重的炎症综合征，通常是致命的，其特点是过度免疫激活导致发热、细胞减少和多器官受累。免疫检查点抑制剂（ICIs）是许多当代癌症治疗方案的核心，但其使用与免疫相关不良事件有关。在此，我们报告了一例单药地塞米松成功治疗 ICI 诱导的 HLH 病例，并对 ICI 诱导的 HLH 病例进行了文献综述，重点关注治疗策略和结果。我们使用 Medline 数据库搜索了 ICI 相关 HLH 病例，2017 年至 2023 年间共报道了 51 例。我们的研究结果凸显了这种疾病的严重性，51 例病例报告中的死亡率为 13.7%。ICI诱发的HLH的治疗策略各不相同：单纯类固醇（56.9%）、类固醇联合依托泊苷（17.6%）、类固醇联合托珠单抗（11.8%）以及其他组合。我们的文献综述显示，在某些 ICI-HLH 病例中，单用类固醇治疗可能就足够了，单用类固醇治疗的死亡率（29 例）（13.8%）与同时使用类固醇和免疫调节剂治疗的死亡率（15 例，13.3%）相当。此外，所有接受类固醇和托珠单抗治疗的患者都存活了下来（n = 6），这表明当类固醇单药治疗效果不佳时，托珠单抗可能是合理的下一步治疗方案。我们就 ICI 罕见并发症的调查和治疗提出了建议。最后，我们讨论了未来可能采取的方法，为 ICI 诱导的 HLH 的诊断和管理制定循证策略，包括整合患者社区参与的重要性。

{"title":"Hemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitor use: A review of the current knowledge and future directions","authors":"Charlotte S. Walmsley , Zachary Schoepflin , Charlotte De Brabandt , Deepa Rangachari , Shana Berwick , Rushad Patell","doi":"10.1016/j.bcmd.2024.102896","DOIUrl":"10.1016/j.bcmd.2024.102896","url":null,"abstract":"<div><div>Hemophagocytic lymphohistiocytosis (HLH) is a severe and often lethal inflammatory syndrome characterized by excessive immune activation leading to fever, cytopenias, and multiorgan involvement. Immune checkpoint inhibitors (ICIs) are central to many contemporary cancer regimens, but their use is associated with immune-related adverse events. Here, we report a case of ICI-induced HLH successfully treated with single agent dexamethasone and provide a scoping review of the literature for cases of ICI-induced HLH with a focus on treatment strategies and outcomes. Using the Medline database, we searched for cases of ICI-associated HLH, with a total of 51 cases reported between 2017 and 2023. Our results underscore the severe nature of this disease, with a 13.7 % mortality rate across 51 case reports. Treatment strategies for ICI-induced HLH were variable: steroids alone (56.9 %), steroids with etoposide (17.6 %), steroids with tociluzumab (11.8 %), among other combinations. Our literature review indicates that steroids alone may be sufficient treatment in some cases of ICI-HLH, with comparable mortality with steroids alone (<em>n</em> = 29) (13.8 %) to that of cases treated with both steroids and immunomodulators (<em>n</em> = 15, 13.3 %). Moreover, all patients treated with steroids and tocilizumab survived (<em>n</em> = 6), suggesting that tocilizumab may be a reasonable next line of therapy when steroid monotherapy proves inadequate. We propose an outline for investigation and treatment of this rare complication of ICI use. Finally, we discuss possible future approaches to develop evidence-based strategies for the diagnosis and management of ICI-induced HLH including the importance of integrating the role of patient community involvement.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102896"},"PeriodicalIF":2.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Further biological characterization of small molecules UM171 and SR1: In vitro effects on three hematopoietic cell populations from human cord blood 小分子 UM171 和 SR1 的进一步生物学特征：对人类脐带血中三种造血细胞群的体外效应。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-09-18 DOI: 10.1016/j.bcmd.2024.102895

Patricia Flores-Guzman, Aranxa Torres-Caballero, Hector Mayani

Small molecules UM171 and SR1 have already been taken into clinically-oriented protocols for the ex vivo expansion of hematopoietic stem (HSCs) and progenitor (HPCs) cells. In order to gain further insight into their biology, in the present study we have assessed their effects, both individually and in combination, on the in vitro long-term proliferation and expansion of HSCs and HPCs contained within three different cord blood-derived cell populations: MNCs (CD34⁺ cells = 0.8 %), LIN⁻ cells (CD34⁺ cells = 41 %), and CD34⁺ cells (CD34⁺ cells >98 %). Our results show that when added to cultures in the absence of recombinant stimulatory cytokines, neither molecule had any effect. In contrast, when added in the presence of hematopoietic cytokines, UM171 and SR1 had significant stimulatory effects on cell proliferation and expansion in cultures of LIN⁻ and CD34⁺ cells. No significant effects were observed in cultures of MNCs. The effects of both molecules were more pronounced in cultures with the highest proportion of CD34⁺ cells, and the greatest effects were observed when both molecules were added in combination. In the absence of small molecules, cell numbers reached a peak by days 25–30, and then declined; whereas in the presence of UM171 or/and SR1 cell numbers were sustained up to day 45 of culture. Our results indicate that besides CD34⁺ cells, LIN⁻ cells could also be used as input cells in clinically-oriented expansion protocols, and that using both molecules simultaneously would be a better approach than using only one of them.

小分子 UM171 和 SR1 已被临床应用于体内外造血干细胞（HSCs）和祖细胞（HPCs）的扩增。为了进一步了解它们的生物学特性，我们在本研究中评估了它们单独或联合使用对三种不同脐带血细胞群中造血干细胞和造血祖细胞体外长期增殖和扩增的影响：MNCs（CD34+细胞=0.8%）、LIN-细胞（CD34+细胞=41%）和CD34+细胞（CD34+细胞>98%）。我们的研究结果表明，在没有重组刺激细胞因子的情况下，向培养物中添加这两种分子都不会产生任何影响。相反，当加入造血细胞因子时，UM171 和 SR1 对 LIN- 和 CD34+ 细胞培养物中的细胞增殖和扩增有显著的刺激作用。在 MNCs 培养中未观察到明显作用。在 CD34+ 细胞比例最高的培养物中，两种分子的作用更为明显，当两种分子联合添加时，观察到的作用最大。在没有小分子的情况下，细胞数量在第 25-30 天达到峰值，然后下降；而在有 UM171 或/和 SR1 的情况下，细胞数量可维持到培养的第 45 天。我们的研究结果表明，除了 CD34+ 细胞，LIN- 细胞也可用作临床导向扩增方案的输入细胞，同时使用两种分子比只使用其中一种分子更好。

{"title":"Further biological characterization of small molecules UM171 and SR1: In vitro effects on three hematopoietic cell populations from human cord blood","authors":"Patricia Flores-Guzman, Aranxa Torres-Caballero, Hector Mayani","doi":"10.1016/j.bcmd.2024.102895","DOIUrl":"10.1016/j.bcmd.2024.102895","url":null,"abstract":"<div><div>Small molecules UM171 and SR1 have already been taken into clinically-oriented protocols for the ex vivo expansion of hematopoietic stem (HSCs) and progenitor (HPCs) cells. In order to gain further insight into their biology, in the present study we have assessed their effects, both individually and in combination, on the in vitro long-term proliferation and expansion of HSCs and HPCs contained within three different cord blood-derived cell populations: MNCs (CD34<sup>+</sup> cells = 0.8 %), LIN<sup>−</sup> cells (CD34<sup>+</sup> cells = 41 %), and CD34<sup>+</sup> cells (CD34<sup>+</sup> cells >98 %). Our results show that when added to cultures in the absence of recombinant stimulatory cytokines, neither molecule had any effect. In contrast, when added in the presence of hematopoietic cytokines, UM171 and SR1 had significant stimulatory effects on cell proliferation and expansion in cultures of LIN<sup>−</sup> and CD34<sup>+</sup> cells. No significant effects were observed in cultures of MNCs. The effects of both molecules were more pronounced in cultures with the highest proportion of CD34<sup>+</sup> cells, and the greatest effects were observed when both molecules were added in combination. In the absence of small molecules, cell numbers reached a peak by days 25–30, and then declined; whereas in the presence of UM171 or/and SR1 cell numbers were sustained up to day 45 of culture. Our results indicate that besides CD34<sup>+</sup> cells, LIN<sup>−</sup> cells could also be used as input cells in clinically-oriented expansion protocols, and that using both molecules simultaneously would be a better approach than using only one of them.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102895"},"PeriodicalIF":2.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Growth hormone is involved in GATA1 gene expression via STAT5B in human erythroleukemia and monocytic cell lines 生长激素通过 STAT5B 参与人类红细胞白血病和单核细胞系中 GATA1 基因的表达。

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-09-18 DOI: 10.1016/j.bcmd.2024.102894

Mana Mitsutani , Mei Yokoyama , Hiromi Hano , Aoi Morita , Midori Matsushita , Tetsuya Tagami , Kenji Moriyama

GATAs are a family of transcription factors consisting of six members. Particularly, GATA1 and GATA2 have been reported to promote the development of erythrocytes, megakaryocytes, eosinophils, and mast cells. However, little information is available on the extracellular ligands that promote GATA1 expression. We evaluated whether growth hormone (GH) is an extracellular stimulator that participates in the signal transduction of GATAs, focusing on GATA1 expression in hematopoietic cell lineages. We used a reporter assay, RT-PCR, real-time quantitative PCR, and western blotting to evaluate GH-induced expression of GATA1 and GATA2 in the human erythroleukemic cell line K562 and the non-erythroid cell line U937. GATA1 expression in these hematopoietic cell lines increased at the transcriptional and protein levels in the presence of GH, and was inhibited by a STAT5 specific inhibitor. Cells transfected with activated STAT5B showed increased expression of GATA1. We identified functional STAT5B consensus sequences as binding site-158 bp from the transcription starting site in the GATA1 promoter region. These results suggest that GH directly induces GATA1 expression via GHR/JAK/STAT5 and is related to hematopoietic cell proliferation.

GATA 是一个转录因子家族，由六个成员组成。据报道，GATA1 和 GATA2 尤其能促进红细胞、巨核细胞、嗜酸性粒细胞和肥大细胞的发育。然而，有关促进 GATA1 表达的细胞外配体的信息却很少。我们评估了生长激素（GH）是否是参与 GATA 信号转导的细胞外刺激物，重点研究了造血细胞系中 GATA1 的表达。我们使用了报告基因检测法、RT-PCR、实时定量 PCR 和 Western 印迹法来评估 GH 诱导的 GATA1 和 GATA2 在人红细胞白血病细胞系 K562 和非红细胞白血病细胞系 U937 中的表达。在 GH 存在的情况下，这些造血细胞系中 GATA1 的表达在转录和蛋白水平上都有所增加，并受到 STAT5 特异性抑制剂的抑制。转染了活化的 STAT5B 的细胞显示 GATA1 的表达增加。我们确定了功能性 STAT5B 共识序列，即 GATA1 启动子区域中距转录起始位点 158 bp 的结合位点。这些结果表明，GH 通过 GHR/JAK/STAT5 直接诱导 GATA1 的表达，并与造血细胞增殖有关。

{"title":"Growth hormone is involved in GATA1 gene expression via STAT5B in human erythroleukemia and monocytic cell lines","authors":"Mana Mitsutani , Mei Yokoyama , Hiromi Hano , Aoi Morita , Midori Matsushita , Tetsuya Tagami , Kenji Moriyama","doi":"10.1016/j.bcmd.2024.102894","DOIUrl":"10.1016/j.bcmd.2024.102894","url":null,"abstract":"<div><div>GATAs are a family of transcription factors consisting of six members. Particularly, GATA1 and GATA2 have been reported to promote the development of erythrocytes, megakaryocytes, eosinophils, and mast cells. However, little information is available on the extracellular ligands that promote GATA1 expression. We evaluated whether growth hormone (GH) is an extracellular stimulator that participates in the signal transduction of GATAs, focusing on GATA1 expression in hematopoietic cell lineages. We used a reporter assay, RT-PCR, real-time quantitative PCR, and western blotting to evaluate GH-induced expression of GATA1 and GATA2 in the human erythroleukemic cell line K562 and the non-erythroid cell line U937. GATA1 expression in these hematopoietic cell lines increased at the transcriptional and protein levels in the presence of GH, and was inhibited by a STAT5 specific inhibitor. Cells transfected with activated STAT5B showed increased expression of GATA1. We identified functional STAT5B consensus sequences as binding site-158 bp from the transcription starting site in the GATA1 promoter region. These results suggest that GH directly induces GATA1 expression via GHR/JAK/STAT5 and is related to hematopoietic cell proliferation.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102894"},"PeriodicalIF":2.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies 出血诊断难题的表型和基因型评估：两个案例研究

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2024-09-10 DOI: 10.1016/j.bcmd.2024.102893

Sean X. Gu , Ayesha Butt , Vincent P. Schulz , Henry M. Rinder , Alfred I. Lee , Patrick G. Gallagher , John Hwa , Robert D. Bona

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.

遗传性血小板疾病（IPDs）是一类异质性疾病，给诊断和治疗带来了巨大挑战。在此，我们报告了两例临床出血症状明显但常规临床实验室检测病因不明的患者。通过结合使用高维多重质谱和基因测序技术进行进一步评估，发现了这两例患者出血的根本原因，并最终确诊。这些病例凸显了多模式联合方法在评估出血性疾病患者方面的潜在作用。此外，这些高参数方法还能提供实质性的机理见解，并能加深我们对 IPD 分子发病机制的了解。未来还需要对更大的患者群体进行研究，以进一步验证这一策略，将其诊断率和准确性与目前的临床实验室检测方法进行直接比较，从而最终改善患者护理。

{"title":"Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies","authors":"Sean X. Gu , Ayesha Butt , Vincent P. Schulz , Henry M. Rinder , Alfred I. Lee , Patrick G. Gallagher , John Hwa , Robert D. Bona","doi":"10.1016/j.bcmd.2024.102893","DOIUrl":"10.1016/j.bcmd.2024.102893","url":null,"abstract":"<div><p>Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102893"},"PeriodicalIF":2.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0