Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells
Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells
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DOI：
10.1038/sj.leu.2404401
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发表时间：
2006-12-01
期刊：
影响因子：
11.4
通讯作者：
Givol, D.
中科院分区：
文献类型：
--
作者：
Gal, H.;Amariglio, N.;Givol, D.
肿瘤含有一部分维持疾病传播的癌症干细胞。从急性髓性白血病（AML）中分离的CD 34 + CD 38-细胞被证明是富集的白血病干细胞（LSC）。我们从AML中分离出CD 34 + CD 38-细胞组分，并使用微阵列将其基因表达谱与CD 34 + CD 38+细胞组分进行比较。我们发现409个基因在两个细胞群体之间至少有两倍的过度表达或表达不足。这些包括DNA修复、信号转导和细胞周期基因的低表达，与干细胞的相对静止一致，以及白血病细胞的染色体畸变和突变。LSC表达数据与正常造血干细胞（HSC）的表达数据的比较显示，34%的调节基因由LSC和HSC共享，支持LSC起源于HSC祖细胞内的建议。我们专注于Notch途径，因为发现Notch配体Jagged-2在LSC样品中过表达。我们表明，DAPT，一种γ-分泌酶，蛋白酶，参与锯齿和Notch信号，抑制LSC的生长在菌落形成试验。鉴定调节LSC自我更新的其他基因可能为治疗提供新的靶点。
Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34+CD38- cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34+CD38- cell fraction from AML and compared their gene expression profiles to the CD34+CD38+ cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.