Pub Date : 2025-02-07DOI: 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.
{"title":"Hereditary disorders of ineffective erythropoiesis","authors":"Richard A. King , Rami Khoriaty","doi":"10.1016/j.bcmd.2025.102910","DOIUrl":"10.1016/j.bcmd.2025.102910","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"111 ","pages":"Article 102910"},"PeriodicalIF":2.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388100","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}
Pub Date : 2025-02-07DOI: 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.
{"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}
Pub Date : 2025-01-16DOI: 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.
{"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}
Pub Date : 2024-12-17DOI: 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.
{"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}
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.
{"title":"Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1)","authors":"Alexandre Raynor , Katell Peoc'h , Camille Boi , Hana Manceau , Serge Pissard , Karim Diallo , Caroline Kannengiesser , Pierre Rohrlich","doi":"10.1016/j.bcmd.2024.102898","DOIUrl":"10.1016/j.bcmd.2024.102898","url":null,"abstract":"<div><div>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 <em>SLC11A2</em> 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 <em>DMT1</em> variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of <em>SLC11A2</em> (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.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"110 ","pages":"Article 102898"},"PeriodicalIF":2.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614339","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}
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.
{"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}
Pub Date : 2024-09-30DOI: 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.
{"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}
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.
{"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}
Pub Date : 2024-09-18DOI: 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.
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