{"title":"CREB3L1参与了JAK2第12外显子突变诱导的红细胞生成。","authors":"","doi":"10.1016/j.exphem.2024.104636","DOIUrl":null,"url":null,"abstract":"<div><div><em>CREB3L1</em>, a gene encoding the endoplasmic reticulum stress transducer, is specifically overexpressed in platelet RNA from patients with myeloproliferative neoplasms (MPNs). However, the pathophysiological roles of <em>CREB3L1</em> overexpression remain unclear. In the present study, we aimed to study <em>CREB3L1</em> messenger RNA (mRNA) expression in the red blood cells (RBCs) of patients with MPN and its role in erythrocytosis. Elevated expression of <em>CREB3L1</em> was exclusively observed in the RBCs of patients with polycythemia vera (PV) harboring <em>JAK2</em> exon 12 mutations, but not in those harboring <em>JAK2</em> V617F mutation or control subjects. In erythropoiesis, <em>CREB3L1</em> expression was sharply induced in erythroblasts of bone marrow cells collected from patients with <em>JAK2</em> exon 12 mutation. This was also evident when erythropoiesis was induced in vitro using hematopoietic stem and progenitor cells (HSPCs) with <em>JAK2</em> exon 12 mutation. Interestingly, overexpression of <em>CREB3L1</em> in RBCs was observed in patients with reactive erythrocytosis whose serum erythropoietin (EPO) levels exceeded 100 mIU/mL. Elevated <em>CREB3L1</em> expression was also observed in the erythroblasts of a patient with acute erythroid leukemia. EPO-dependent induction of <em>CREB3L1</em> was evident in erythroblasts differentiated from HSPCs in vitro, regardless of driver mutation status or MPN pathogenesis. These data strongly suggest that <em>CREB3L1</em> overexpression in RBCs is associated with hyperactivation of the EPO receptor and its downstream molecule, JAK2. Short hairpin RNA (shRNA) knockdown of <em>CREB3L1</em> expression in HSPCs blocked erythroblast formation in vitro. These results suggest that <em>CREB3L1</em> is required for erythropoiesis in the presence of <em>JAK2</em> exon 12 mutation or high level of EPO, possibly by antagonizing cellular stress.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Involvement of CREB3L1 in erythropoiesis induced by JAK2 exon 12 mutation\",\"authors\":\"\",\"doi\":\"10.1016/j.exphem.2024.104636\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div><em>CREB3L1</em>, a gene encoding the endoplasmic reticulum stress transducer, is specifically overexpressed in platelet RNA from patients with myeloproliferative neoplasms (MPNs). However, the pathophysiological roles of <em>CREB3L1</em> overexpression remain unclear. In the present study, we aimed to study <em>CREB3L1</em> messenger RNA (mRNA) expression in the red blood cells (RBCs) of patients with MPN and its role in erythrocytosis. Elevated expression of <em>CREB3L1</em> was exclusively observed in the RBCs of patients with polycythemia vera (PV) harboring <em>JAK2</em> exon 12 mutations, but not in those harboring <em>JAK2</em> V617F mutation or control subjects. In erythropoiesis, <em>CREB3L1</em> expression was sharply induced in erythroblasts of bone marrow cells collected from patients with <em>JAK2</em> exon 12 mutation. This was also evident when erythropoiesis was induced in vitro using hematopoietic stem and progenitor cells (HSPCs) with <em>JAK2</em> exon 12 mutation. Interestingly, overexpression of <em>CREB3L1</em> in RBCs was observed in patients with reactive erythrocytosis whose serum erythropoietin (EPO) levels exceeded 100 mIU/mL. Elevated <em>CREB3L1</em> expression was also observed in the erythroblasts of a patient with acute erythroid leukemia. EPO-dependent induction of <em>CREB3L1</em> was evident in erythroblasts differentiated from HSPCs in vitro, regardless of driver mutation status or MPN pathogenesis. These data strongly suggest that <em>CREB3L1</em> overexpression in RBCs is associated with hyperactivation of the EPO receptor and its downstream molecule, JAK2. Short hairpin RNA (shRNA) knockdown of <em>CREB3L1</em> expression in HSPCs blocked erythroblast formation in vitro. These results suggest that <em>CREB3L1</em> is required for erythropoiesis in the presence of <em>JAK2</em> exon 12 mutation or high level of EPO, possibly by antagonizing cellular stress.</div></div>\",\"PeriodicalId\":12202,\"journal\":{\"name\":\"Experimental hematology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental hematology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0301472X24005010\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental hematology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0301472X24005010","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Involvement of CREB3L1 in erythropoiesis induced by JAK2 exon 12 mutation
CREB3L1, a gene encoding the endoplasmic reticulum stress transducer, is specifically overexpressed in platelet RNA from patients with myeloproliferative neoplasms (MPNs). However, the pathophysiological roles of CREB3L1 overexpression remain unclear. In the present study, we aimed to study CREB3L1 messenger RNA (mRNA) expression in the red blood cells (RBCs) of patients with MPN and its role in erythrocytosis. Elevated expression of CREB3L1 was exclusively observed in the RBCs of patients with polycythemia vera (PV) harboring JAK2 exon 12 mutations, but not in those harboring JAK2 V617F mutation or control subjects. In erythropoiesis, CREB3L1 expression was sharply induced in erythroblasts of bone marrow cells collected from patients with JAK2 exon 12 mutation. This was also evident when erythropoiesis was induced in vitro using hematopoietic stem and progenitor cells (HSPCs) with JAK2 exon 12 mutation. Interestingly, overexpression of CREB3L1 in RBCs was observed in patients with reactive erythrocytosis whose serum erythropoietin (EPO) levels exceeded 100 mIU/mL. Elevated CREB3L1 expression was also observed in the erythroblasts of a patient with acute erythroid leukemia. EPO-dependent induction of CREB3L1 was evident in erythroblasts differentiated from HSPCs in vitro, regardless of driver mutation status or MPN pathogenesis. These data strongly suggest that CREB3L1 overexpression in RBCs is associated with hyperactivation of the EPO receptor and its downstream molecule, JAK2. Short hairpin RNA (shRNA) knockdown of CREB3L1 expression in HSPCs blocked erythroblast formation in vitro. These results suggest that CREB3L1 is required for erythropoiesis in the presence of JAK2 exon 12 mutation or high level of EPO, possibly by antagonizing cellular stress.
期刊介绍:
Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.