Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.
Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.
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DOI：
10.1038/s41467-023-40961-z
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发表时间：
2023-08-24
影响因子：
16.6
通讯作者：
Sanchez-Garcia, Isidro
中科院分区：
文献类型：
--
作者：
Isidro-Hernandez, Marta;Casado-Garcia, Ana;Oak, Ninad;Aleman-Arteaga, Silvia;Ruiz-Corzo, Belen;Martinez-Cano, Jorge;Mayado, Andrea;Sanchez, Elena G.;Blanco, Oscar;Gaspar, Ma Luisa;Orfao, Alberto;Alonso-Lopez, Diego;De Las Rivas, Javier;Riesco, Susana;Prieto-Matos, Pablo;Gonzalez-Murillo, Africa;Criado, Francisco Javier Garcia;Cenador, Maria Begona Garcia;Ramirez-Orellana, Manuel;de Andres, Belen;Vicente-Duenas, Carolina;Cobaleda, Cesar;Nichols, Kim E.;Sanchez-Garcia, Isidro
B细胞急性淋巴细胞白血病（B-ALL）发展的最初步骤通常在儿童中被忽视。几项临床前研究表明，暴露于免疫应激物会触发白血病前期B细胞转化为成熟的B-ALL，但这是如何发生的仍然是一个长期存在且未解决的挑战。在这里，我们表明先天免疫失调在恶性前Pax 5 +/− B细胞前体向白血病的克隆进化中起着驱动作用。转录谱显示，Myd 88在免疫应激的癌前B细胞前体和白血病细胞中下调。Myd 88表达的遗传减少通过炎症依赖性机制导致Pax 5 +/− Myd 88 +/−小鼠中白血病发病率显著增加。Myd 88非依赖性Toll样受体3信号的早期诱导导致Pax 5 +/−小鼠白血病发展的显著延迟总之，这些发现确定了先天免疫失调在白血病中的作用，对理解和治疗儿童白血病前状态具有重要意义。免疫应激与白血病前期B细胞向B细胞急性淋巴细胞白血病的转化有关。在这里，作者显示了白血病前体B细胞先天免疫信号的失调，并与小鼠模型中B细胞急性淋巴细胞白血病的发展有关。
The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/− B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/−Myd88+/− mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/− mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children. Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.
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影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
5.9
作者：
FAITH, DP
通讯作者：
FAITH, DP
影响因子：
8.8
作者：
Ajrouche, R.;Rudant, J.;Orsi, L.;Petit, A.;Baruchel, A.;Lambilliotte, A.;Gambart, M.;Michel, G.;Bertrand, Y.;Ducassou, S.;Gandemer, V.;Paillard, C.;Saumet, L.;Blin, N.;Hemon, D.;Clavel, J.
通讯作者：
Clavel, J.
影响因子：
11.2
作者：
Case, Marian;Matheson, Elizabeth;Irving, Julie A. E.
通讯作者：
Irving, Julie A. E.