Decoupling of Tumor-Initiating Activity from Stable Immunophenotype in HoxA9-Meis1-Driven AML

被引:50
作者
Gibbs, Kenneth D., Jr. [1 ,2 ]
Jager, Astraea [1 ]
Crespo, Oliver [1 ,2 ]
Goltsev, Yury [1 ]
Trejo, Angelica [1 ]
Richard, Chase E. [1 ]
Nolan, Garry P. [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA
[2] Stanford Univ, Sch Med, Program Immunol, Stanford, CA 94305 USA
关键词
ACUTE MYELOID-LEUKEMIA; CANCER STEM-CELLS; EVOLUTION; HIERARCHY; CYTOMETRY; GENE; RARE;
D O I
10.1016/j.stem.2012.01.004
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Increasing evidence suggests tumors are maintained by cancer stem cells; however, their nature remains controversial. In a HoxA9-Meis1 (H9M) model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy-stem/progenitor cells (Lin(-)kit(+)) and committed progenitors of the myeloid (Gr1(+)kit(+)) and lymphoid lineages (Lym(+)kit(+)). These distinct tumor-initiating cells (TICs) clonally recapitulated the immunophenotypic spectrum of the original tumor in vivo (including cells with a less-differentiated immunophenotype) and shared signaling networks, such that in vivo pharmacologic targeting of conserved TIC survival pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, this suggests that in certain malignancies tumor-initiation activity (or "cancer stemness") can represent a cellular state that exists independently of distinct immunophenotypic definition.
引用
收藏
页码:210 / 217
页数:8
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