Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura
{"title":"JAK2V617F 会损害骨髓增殖性肿瘤中的淋巴分化","authors":"Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura","doi":"10.1038/s41375-024-02388-3","DOIUrl":null,"url":null,"abstract":"<p>Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, <i>JAK2</i><sup>V617F</sup>, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how <i>JAK2</i><sup>V617F</sup> hematopoiesis affects lymphoid differentiation in MPNs.</p><p>To assess the effect of <i>JAK2</i><sup>V617F</sup> on hematopoiesis in our MPN cohort, we measured <i>JAK2</i><sup>V617F</sup> mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45<sup>dim</sup>CD34<sup>+</sup>CD38<sup>-</sup>CD45RA<sup>-</sup>) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of <i>JAK2</i><sup>V617F</sup> hematopoiesis, <i>JAK2</i><sup>V617F</sup> was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in <i>JAK2</i><sup>V617F</sup> MPNs.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms\",\"authors\":\"Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura\",\"doi\":\"10.1038/s41375-024-02388-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, <i>JAK2</i><sup>V617F</sup>, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how <i>JAK2</i><sup>V617F</sup> hematopoiesis affects lymphoid differentiation in MPNs.</p><p>To assess the effect of <i>JAK2</i><sup>V617F</sup> on hematopoiesis in our MPN cohort, we measured <i>JAK2</i><sup>V617F</sup> mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45<sup>dim</sup>CD34<sup>+</sup>CD38<sup>-</sup>CD45RA<sup>-</sup>) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of <i>JAK2</i><sup>V617F</sup> hematopoiesis, <i>JAK2</i><sup>V617F</sup> was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in <i>JAK2</i><sup>V617F</sup> MPNs.</p>\",\"PeriodicalId\":18109,\"journal\":{\"name\":\"Leukemia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41375-024-02388-3\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-024-02388-3","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms
Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how JAK2V617F hematopoiesis affects lymphoid differentiation in MPNs.
To assess the effect of JAK2V617F on hematopoiesis in our MPN cohort, we measured JAK2V617F mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45dimCD34+CD38-CD45RA-) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of JAK2V617F hematopoiesis, JAK2V617F was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in JAK2V617F MPNs.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues