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标题：The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia
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作者：Marius Külp ; Anna Lena Siemund ; Patrizia Larghero 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：7
页码：1-26
DOI：10.1016/j.isci.2022.104613
语种：English
出版社：Elsevier
摘要：SummaryThe most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenesKMT2A:AFF1andAFF1:KMT2A, respectively.KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevatedICOSLGexpression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.Graphical abstractDisplay OmittedHighlights•Early growth response 3 (EGR3) is a direct transactivator of the immune checkpoint geneICOSLG•highICOSLGexpression at diagnosis is predictive for ALL relapse•EGR3andICOSLGexpressions are relapse-associated•expression of ICOSLG on t(4;11) ALL cells leads to the rapid expansion of TregsHealth sciences; Immunology; Cancer