Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia
Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia
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DOI：
10.1182/blood-2008-10-182071
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发表时间：
2009-12-24
期刊：
影响因子：
20.3
通讯作者：
Tenen, Daniel G.
中科院分区：
文献类型：
--
作者：
Guibal, Florence C.;Alberich-Jorda, Meritxell;Tenen, Daniel G.
急性早幼粒细胞白血病(APL)的特征是骨髓和血液中的早幼粒细胞分化和积聚受阻。大多数APL患者存在t(15：17)易位，导致融合蛋白早幼粒细胞-维甲酸受体α的表达。维甲酸治疗可导致早幼粒细胞-维甲酸受体α蛋白降解，白血病细胞消失；然而，30%的APL患者治疗后复发。复发的一个潜在机制是治疗后癌症干细胞在造血器官中的持续存在。使用我们开发的一种新的分选策略来分离不同分化阶段的小鼠髓系细胞，我们在APL小鼠模型中鉴定了聚集在脾和骨髓中的定向髓系细胞群(CD34(+)，c-kit(+)，Fc-Gamma RIII/II+，Gr1(Int))。我们观察到这些细胞能够有效地在受体小鼠中产生白血病，表明这个群体代表了APL癌症启动细胞。这些细胞可能通过甲基化依赖的机制下调转录因子CCAAT/增强子结合蛋白α(C/EBPα)，表明C/EBPα去调控有助于APL癌症启动细胞的转化。我们的发现通过证明一个致力于转化的祖细胞可以启动和传播疾病，从而提供了对APL生物学的进一步理解。(血。2009；114：5415-5425)
Acute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15: 17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor alpha. Treatment with retinoic acid leads to degradation of promyelocytic-retinoic acid receptor alpha protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer "stem" cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34(+), c-kit(+), Fc gamma RIII/II+, Gr1(int)) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer-initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein alpha (C/EBP alpha) possibly through a methylation-dependent mechanism, indicating that C/EBP alpha deregulation contributes to transformation of APL cancer-initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease. (Blood. 2009; 114: 5415-5425)