Blood Cells Molecules and Diseases最新文献

英文中文

Culprit or innocent bystander? The case of a new fast-moving hemoglobin J variant in a pregnant woman

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2025-03-12 DOI: 10.1016/j.bcmd.2025.102920

Ilaria Cerroni , Valeria Renola , Alessia Micalizzi , Ester Romanelli , Lucrezia De Marchi , Giorgia Ranucci , Flavia Mallegni , Elisa Meddi , Federico Moretti , Camilla Page , Antonietta Viola , Giovangiacinto Paterno , Maria Ilaria Del Principe , Stefania Casciani , Adriano Venditti , Sergio Bernardini , Antonio Novelli , Maria Teresa Voso , Carmelo Gurnari

引用次数: 0

Unveiling the role of RPS17 and SLC4A1 in diamond-Blackfan Anemia: A zebrafish-based study

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2025-02-25 DOI: 10.1016/j.bcmd.2025.102912

Kyeongmin Kim , Hyerin Lee , Soyul Ahn , Yun Hak Kim , Chang-Kyu Oh

Diamond-Blackfan Anemia (DBA) is a rare congenital disorder characterized by macrocytic anemia, physical abnormalities, and growth delays. Although RPS19 mutations have been more extensively studied in DBA compared to other ribosomal protein genes, the pathological mechanisms of genes such as RPS17 remain largely unexplored. This study aimed to investigate the role of RPS17 haploinsufficiency in DBA, focusing on its downstream effects on erythropoiesis and the involvement of SLC4A1, a critical erythrocyte membrane protein essential for red blood cell stability. Transcriptomic analysis of publicly available RNA sequencing data from DBA patients revealed significant downregulation of SLC4A1 in RPS17-mutated cases. To validate these findings, we generated a zebrafish model of DBA by knocking down rps17 using morpholino injections. Zebrafish embryos with rps17 knockdown exhibited reduced erythropoiesis, impaired hemoglobin synthesis, consistent with DBA. Further analysis confirmed decreased slc4a1a expression in rps17-morphants. Independent knockdown of slc4a1a in zebrafish resulted in similar erythropoietic defects, highlighting its critical role in red blood cell membrane integrity and function. This study identifies slc4a1 as a key downstream target of RPS17 haploinsufficiency and provides novel insights into the molecular mechanisms of DBA. By establishing zebrafish as an effective in vivo model, this research offers potential therapeutic targets for treating DBA and related erythropoietic disorders.

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引用次数: 0

Hereditary disorders of ineffective erythropoiesis

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases

Pub Date : 2025-02-07 DOI: 10.1016/j.bcmd.2025.102910

Richard A. King , Rami Khoriaty

Under steady state conditions, humans must produce ∼2 million red blood cells per second to sustain normal red blood cell counts and hemoglobin levels. Ineffective erythropoiesis, also termed dyserythropoiesis, is a process by which erythroid precursors die or fail to efficiently differentiate in the bone marrow. Ineffective erythropoiesis is characterized by expanded bone marrow erythropoiesis and increased erythroferrone production by bone marrow erythroblasts, with the latter resulting in reduced hepcidin production and increased iron absorption. Ineffective erythropoiesis may result from acquired and congenital conditions. Inherited causes of ineffective erythropoiesis include β-thalassemia, sideroblastic anemias, pyruvate kinase deficiency, and congenital dyserythropoietic anemias. This manuscript reviews the definition and evidence for ineffective erythropoiesis and describes the most common hereditary disorders of dyserythropoiesis.

引用次数: 0

Immunodeficiency in children with Diamond Blackfan and Diamond Blackfan like anemia

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.

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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。

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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

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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。

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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。

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