p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL-leukemia.
p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL-leukemia.
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DOI：
10.1016/j.molonc.2013.07.011
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发表时间：
2013-12
影响因子：
6.6
通讯作者：
Zhang, Jiwang
中科院分区：
文献类型：
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作者：
Zhang, Jun;Seet, Christopher S.;Sun, Clare;Li, Jing;You, Dewen;Volk, Andrew;Breslin, Peter;Li, Xingyu;Wei, Wei;Qian, Zhijian;Zeleznik-Le, Nancy J.;Zhang, Zhou;Zhang, Jiwang
MLL融合基因通过HOXA9和MEIS1等正常MLL靶基因的失控导致白血病的发生。在MLL融合基因诱导的白血病发生中，HOXA9和Meis1都是必需的。HOXA9和Meis1共表达可诱发急性髓系白血病(AML)，类似于MLL融合基因过度表达的小鼠。P27kip1(以下简称p27)是细胞周期的负调控因子，也被定义为MLL靶点，在MLL白血病细胞(LCS)中表达上调。为了探讨p27在MLL白血病发病机制中的作用，我们检测了p27缺失(p27-/-)对MLL-AF9(MA9)诱导的小鼠AML发生的影响。以HOXA9/Meis1(H/M)、p27野生型(p27+/+)和p27-/-AML为对照。我们发现MA9-AML和H/M-AML的LCs都可以分为三个组分，CD117-CD11bhi分化组分以及CD117+CD11bhi和CD117+CD11blo两个分化较低的组分。CD117+CD11blo仅占LC总数的1-3%，与其他LC相比，其早期造血祖细胞标志物表达水平较高，但成熟髓系细胞标志物表达水平较低。MA9-LCS的CD117+CD11blo组分表达P27，而H/M-LCS的CD117+CD11blo组分则不表达P27。P27缺失通过减少白血病干细胞(LSCs)的频率显著降低CD117+CD11blo MA9-LCS的致白血病能力，但在H/M-LCS中不这样做。此外，我们还发现p27在两种类型的LC中都高度表达，并且在CD117-CD11bhi组分中是细胞周期停滞所必需的。此外，我们发现c-Myc的表达是维持未分化状态的LCs所必需的，而不依赖于细胞的增殖。我们的结论是，p27抑制LCs的增殖，这是维持一小部分MA9-LSCs的静止和耐药状态所必需的，协同c-Myc的分化阻断功能。
MLL (mixed-lineage leukemia)-fusion genes induce the development of leukemia through deregulation of normal MLL target genes, such as HOXA9 and MEIS1. Both HOXA9 and MEIS1 are required for MLL-fusion gene-induced leukemogenesis. Co-expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL-fusion genes are over-expressed. p27kip1 (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up-regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL-leukemia, we examined the effects of p27 deletion (p27-/-) on MLL-AF9 (MA9)-induced murine AML development. HOXA9/MEIS1 (H/M)-induced, p27 wild-type (p27+/+) and p27-/- AML were studied in parallel as controls. We found that LCs from both MA9-AML and H/M-AML can be separated into three fractions, a CD117-CD11bhi differentiated fraction as well as CD117+CD11bhi and CD117+CD11blo, two less differentiated fractions. The CD117+CD11blo fraction, comprising only 1-3% of total LCs, expresses higher levels of early hematopoietic progenitor markers but lower levels of mature myeloid cell markers compared to other populations of LCs. p27 is expressed and is required for maintaining the quiescent and drug-resistant states of the CD117+CD11blo fraction of MA9-LCs but not of H/M-LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117+CD11blo MA9-LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H/M-LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117-CD11bhi fraction in both types of LCs. Furthermore, we found that c-Myc expression is required for maintaining LCs in an undifferentiated state independently of proliferation. We concluded that p27 represses the proliferation of LCs, which is specifically required for maintaining the quiescent and drug-resistant states of a small subset of MA9-LSCs in collaboration with the differentiation blockage function of c-Myc.
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
8
作者：
Hoffman, B;Amanullah, A;Liebermann, DA
通讯作者：
Liebermann, DA
影响因子：
9.2
作者：
Ernst, P;Mabon, M;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
11.4
作者：
通讯作者：
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