A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1.
A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1.
复制标题
DOI：
10.1016/j.devcel.2017.12.005
复制
发表时间：
2018-02-05
影响因子：
11.8
通讯作者：
Enver T
中科院分区：
文献类型：
--
作者：
Böiers C;Richardson SE;Laycock E;Zriwil A;Turati VA;Brown J;Wray JP;Wang D;James C;Herrero J;Sitnicka E;Karlsson S;Smith AJH;Jacobsen SEW;Enver T
ETV6-RUNX1与儿童急性B淋巴细胞性白血病(CALL)有关，它是一种首发突变，在子宫内引发临床上无症状的白血病前期。由于胚胎和成人的世系承诺等级不同，并且癌基因的影响依赖于细胞上下文，我们假设童年时ETV6-RUNX1 CALL的从属关系反映了其起源于胚胎生命特有的祖细胞。我们对人类早期胚胎中第一批新出现的B细胞进行了鉴定，确定了一个发育受限的CD19IL-7R+祖细胞亚群，它在个体发育过程中从髓系程序过渡到淋巴系程序。这一发育系列在分化人类多能干细胞(HPSCs)方面进行了概述，从而为CALL的启动提供了一个模型。从内源性ETV6基因座表达ETV6-RUNX1的基因组工程hPSC显示CD19−IL-7R+隔室扩大，部分阻断B系承诺，并产生具有异常髓系基因表达特征和潜力的PROB细胞：特征(共同)与白血病前状态一致。人类最早的B系祖细胞的高分辨率鉴定胎儿CD19-IL-7R+祖细胞在发育过程中独特地共表达B/髓系基因hPSC培养中的淋巴承诺概括了表达ETV6-RUNX1的hPSC来源的ProB细胞异常共表达髓系基因Böier，Richardson等人。探讨儿童急性淋巴细胞性白血病发育易感性的可能性。对人胎肝中最早的B细胞前体细胞的表征发现了一个独特的祖细胞隔室，可以用人类多能干细胞来重现，以模拟白血病前启动癌基因ETV6-RUNX1的影响。
ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19−IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19−IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state. High-resolution characterization of the earliest human B lineage progenitors Fetal CD19–IL-7R+ progenitors uniquely co-express B/myeloid genes during development Lymphoid commitment in hPSC culture recapitulates human fetal B lymphopoiesis hPSC-derived proB cells expressing ETV6-RUNX1 aberrantly co-express myeloid genes Böiers, Richardson et al. explore the potential for a developmental susceptibility to childhood acute lymphoblastic leukemia. Characterization of earliest B cell progenitors in human fetal liver identified a unique progenitor compartment that can be recapitulated using human pluripotent stem cells to model the impact of the pre-leukemia-initiating oncogene ETV6-RUNX1.
登录
查看更多内容
影响因子：
30.5
作者：
Katerndahl CDS;Heltemes-Harris LM;Willette MJL;Henzler CM;Frietze S;Yang R;Schjerven H;Silverstein KAT;Ramsey LB;Hubbard G;Wells AD;Kuiper RP;Scheijen B;van Leeuwen FN;Müschen M;Kornblau SM;Farrar MA
通讯作者：
Farrar MA
影响因子：
30.5
作者：
Laurenti E;Doulatov S;Zandi S;Plumb I;Chen J;April C;Fan JB;Dick JE
通讯作者：
Dick JE
影响因子：
11.4
作者：
Horton, S. J.;Jaques, J.;Schuringa, J. J.
通讯作者：
Schuringa, J. J.
影响因子：
11.4
作者：
Iijima, K;Sugita, K;Nakazawa, S
通讯作者：
Nakazawa, S
影响因子：
64.5
作者：
Hanna, Jacob;Markoulaki, Styliani;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf