Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia.
Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia.
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DOI：
10.1084/jem.20180853
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发表时间：
2021-02-01
期刊：
影响因子：
--
通讯作者：
Mead AJ
中科院分区：
文献类型：
--
作者：
Louka E;Povinelli B;Rodriguez-Meira A;Buck G;Wen WX;Wang G;Sousos N;Ashley N;Hamblin A;Booth CAG;Roy A;Elliott N;Iskander D;de la Fuente J;Fordham N;O'Byrne S;Inglott S;Norfo R;Salio M;Thongjuea S;Rao A;Roberts I;Mead AJ
青少年粒单核细胞白血病是一种罕见的儿童癌症，预后不良。通过对血液和骨髓样本的表型、功能和分子分析，Louka等人鉴定并表征了疾病传播群体，为白血病干细胞导向的疾病监测和治疗铺平了道路。青少年粒单核细胞白血病（JMML）是一种预后不良的儿童白血病，通常由RAS通路突变引起。JMML中的细胞层次结构特征不佳，包括白血病干细胞（LSC）的身份。FACS和单细胞RNA测序显示JMML造血干/祖细胞（HSPC）具有显著的异质性，包括异常的Lin− CD 34 + CD 38 − CD 90 + CD 45 RA+群体。单细胞HSPC指数分选和克隆形成试验表明：（1）所有体细胞突变都可以追溯到表型HSC区室，RAS途径突变作为“第一击”，（2）突变是通过克隆进化的线性和分支模式获得的，（3）在复发的分子/临床证据之前，同种异体HSC移植后存在突变型HSPC。干细胞测定揭示了JMML LSC的患者间异质性，其存在于但不限于表型HSC区室中。JMML LSC的RNA测序揭示了干细胞和胎儿基因（HLF，MEIS 1，CNN 3，VNN 2和HMGA 2）以及候选治疗靶点/生物标志物（MTOR，SLC 2A 1和CD 96）的上调，为这种疾病的LSC指导的疾病监测和治疗铺平了道路。
Juvenile myelomonocytic leukemia is a rare cancer of childhood with a poor prognosis. Through phenotypic, functional, and molecular analyses of blood and bone marrow samples, Louka et al. identify and characterize the disease-propagating population(s), paving the way for leukemia stem cell–directed disease monitoring and therapy. Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin−CD34+CD38−CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a “first hit,” (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.
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影响因子：
7.2
作者：
Staudinger M;Humpe A;Gramatzki M
通讯作者：
Gramatzki M
在儿童急性淋巴细胞白血病中，处于免疫表型成熟不同阶段的母细胞具有干细胞特性。
影响因子：
50.3
作者：
le Viseur C;Hotfilder M;Bomken S;Wilson K;Röttgers S;Schrauder A;Rosemann A;Irving J;Stam RW;Shultz LD;Harbott J;Jürgens H;Schrappe M;Pieters R;Vormoor J
通讯作者：
Vormoor J
正常和白血病造血的单细胞分析。
影响因子：
10.6
作者：
Povinelli BJ;Rodriguez-Meira A;Mead AJ
通讯作者：
Mead AJ
影响因子：
23.9
作者：
Prashad SL;Calvanese V;Yao CY;Kaiser J;Wang Y;Sasidharan R;Crooks G;Magnusson M;Mikkola HK
通讯作者：
Mikkola HK
影响因子：
30.8
作者：
Stieglitz E;Taylor-Weiner AN;Chang TY;Gelston LC;Wang YD;Mazor T;Esquivel E;Yu A;Seepo S;Olsen S;Rosenberg M;Archambeault SL;Abusin G;Beckman K;Brown PA;Briones M;Carcamo B;Cooper T;Dahl GV;Emanuel PD;Fluchel MN;Goyal RK;Hayashi RJ;Hitzler J;Hugge C;Liu YL;Messinger YH;Mahoney DH Jr;Monteleone P;Nemecek ER;Roehrs PA;Schore RJ;Stine KC;Takemoto CM;Toretsky JA;Costello JF;Olshen AB;Stewart C;Li Y;Ma J;Gerbing RB;Alonzo TA;Getz G;Gruber T;Golub T;Stegmaier K;Loh ML
通讯作者：
Loh ML