A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile.
A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile.
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DOI：
10.3389/fonc.2022.972323
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
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在白血病中，一种称为白血病干细胞（LSC）的独特的癌症起始细胞亚群被认为是推动群体扩张和肿瘤生长的原因。未能消除LSC可能导致疾病复发，无论非LSC被破坏的数量如何。靶向和消除LSC的第一步是识别和表征它们。将来自患者的急性前体B淋巴母细胞白血病（B-ALL）细胞与荧光葡萄糖类似物2-（N-（7-硝基苯-2-氧杂-1，3-二唑-4-基）氨基）-2-脱氧葡萄糖（NBDG）一起孵育，并基于NBDG摄取进行分选。然后将由葡萄糖摄取定义的细胞亚群连续移植到小鼠中并评估白血病引发能力。使用RNA测序（RNA-Seq）表征这些细胞的基因表达谱。在患者B-ALL样本中鉴定出不同的NBDG-低细胞群体。这些细胞是一个小群体（占整个白血病群体的1.92%），具有较低的HLA表达，并且尺寸（4.0至7.0 μm）小于其余白血病群体。所有移植NBDG-低细胞的小鼠在5 - 14周内发生白血病，而移植NBDG-高细胞的小鼠未发生白血病（p ≤ 0.0001-0.002）。NBDG-低小鼠模型的连续移植导致成功的白血病发展。NBDG培养基（NBDG-med）人群也发生了白血病。有趣的是，使用RNA-Seq对来自患者来源的异种移植物（PDX）模型的NBDG-low和NBDG-med细胞的全面分子表征揭示了2，162个差异表达转录物（DET）（p<0.05）的不同谱，其中70.6%在NBDG-low细胞中下调。DET的层次聚类显示NBDG-低与NBDG-中和NBDG-高组的明显分离，NBDG-低组中显著的转录表达改变与癌症存活一致。总之，在B-ALL中发现了具有低葡萄糖摄取（NBDG-low）的独特细胞亚群。尽管这些细胞具有静止特性，但一旦移植到小鼠体内，就显示出强大的白血病引发能力。虽然NBDG-med细胞也引发白血病，但基因表达谱显示了一个独特的特征，可以清楚地将NBDG-low细胞与NBDG-med和其他白血病群体区分开来。这些结果表明，NBDG-低细胞可能代表静止LSC。这些细胞可以在体内适当的环境中被激活，显示出白血病的启动能力。我们的研究提供了深入了解B-ALL启动和生存的生物学机制。
In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival.
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影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
64.5
作者：
Buszczak M;Signer RA;Morrison SJ
通讯作者：
Morrison SJ
影响因子：
14.9
作者：
Gillespie M;Jassal B;Stephan R;Milacic M;Rothfels K;Senff-Ribeiro A;Griss J;Sevilla C;Matthews L;Gong C;Deng C;Varusai T;Ragueneau E;Haider Y;May B;Shamovsky V;Weiser J;Brunson T;Sanati N;Beckman L;Shao X;Fabregat A;Sidiropoulos K;Murillo J;Viteri G;Cook J;Shorser S;Bader G;Demir E;Sander C;Haw R;Wu G;Stein L;Hermjakob H;D'Eustachio P
通讯作者：
D'Eustachio P
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG
影响因子：
20.3
作者：
Ailles, LE;Gerhard, B;Hogge, DE
通讯作者：
Hogge, DE