PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors.
PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors.
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急性早幼粒细胞白血病(APL)以早幼粒细胞过度增殖为特征，致力于向粒细胞的终末分化，使其成为研究非原始细胞类型转化潜力的理想疾病。我们利用小鼠急性早幼粒细胞白血病模型，其中PML-RARα癌基因表达来自内源性组织蛋白酶G启动子，以验证白血病干细胞活性存在于分化的早幼粒细胞间的假设。我们前瞻性地纯化了不同疾病阶段转基因小鼠的早幼粒细胞，并观察到表达PML-RARα的幼年白血病前期小鼠的早幼粒细胞在体外和体内都获得了自我更新的特性。进展为急性白血病与早幼粒细胞隔室的扩大有关，而损害了其他干细胞、祖细胞和终末分化的群体。白血病早幼粒细胞表现出自我更新的特性，并能够在二次受体小鼠中产生白血病。这些数据表明，PML-RARα本身可以在疾病发生之前赋予承诺的造血祖细胞自我更新的特性。这些发现与癌症干细胞可能来自缺乏干细胞特性的承诺的祖细胞的假设是一致的，前提是癌症进展中的起始突变激活了赋予自我更新特性的程序。
Acute promyelocytic leukemia (APL) is characterized by hyperproliferation of promyelocytes, progenitors that are committed to terminal differentiation into granulocytes, making it an ideal disease in which to study the transforming potential of less primitive cell types. We utilized a murine model of APL in which the PML-RARα oncogene is expressed from the endogenous Cathepsin G promoter to test the hypothesis that leukemia stem cell activity resides within the differentiated promyelocyte compartment. We prospectively purified promyelocytes from transgenic mice at various stages of disease and observed that PML-RARα-expressing promyelocytes from young preleukemic mice had acquired properties of self-renewal both in vitro and in vivo. Progression to acute leukemia was associated with an expansion of the promyelocyte compartment at the expense of other stem, progenitor and terminally differentiated populations. Leukemic promyelocytes exhibited properties of self-renewal, and were capable of engendering leukemia in secondary recipient mice. These data indicate that PML-RARα alone can confer properties of self-renewal to committed hematopoietic progenitors prior to the onset of disease. These findings are consistent with the hypothesis that cancer stem cells may arise from committed progenitors that lack stem cell properties, provided that the initiating mutation in cancer progression activates programs that confer properties of self-renewal.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
50.3
作者：
Deguchi, K;Ayton, PM;Gilliland, DG
通讯作者：
Gilliland, DG
影响因子：
20.3
作者：
Neering, Sarah J.;Bushnell, Timothy;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
64.5
作者：
Passegué, E;Wagner, EF;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP