演題抄録

International Symposium

開催概要
開催回
第52回・2014年・横浜
 

Critical pathways for stem cell maintenance and therapeutic strategy in acute myeloid leukemia

演題番号 : TIS2-1

[筆頭演者]
Kitabayashi Issay:1 

1:Division of Mematological Malignancy, National Cancer Center Research Institute

 

Leukemias possess self-renewing stem cells that help to maintain the cancer. The genes encoding transcription factors and epigenetic regulators such as RUNX1, MLL, MOZ, NPM, DNMT3a, TET2 and IDH1/2 are frequently mutated or disrupted by chromosome translocations in acute myeloid leukemia (AML). Whereas such regulators play important roles in establishment and maintenance of hematopoietic stem cells, their mutant forms such as MOZ-fusions contribute to those of leukemia stem cells. Expression of M-CSFR, HOXA9 and c-KIT is high in stem cells of AML. MOZ-fusions induce expression of these genes by interacting with PU.1, c-MYB and BRPF1, respectively, and that these pathways are critical for maintenance of AML stem cells.
Mutations in the specific genes such as NPM, IDH1/2, DNMT3A and FLT3 frequently occur simultaneously in AML patients with normal karyotype. In accordance with these observations, We established a mouse AML model with normal karyotype by co-transducing four mutant genes. Conditional deletion of floxed mutant IDH2 from AML mice blocked 2-HG production and the maintenance of leukemia stem cells, resulting in survival of the AML mice. Metabolome analysis showed that the levels of metabolites involved in TCA cycle and glutamate pathways were lower in AML cells harboring mutant IDH2 than in control cells. Gene-expression analysis indicated that mutant IDH2 and NPMc cooperatively activate Hoxa9/Meis1 and hypoxia pathways to maintain AML cells in vivo. Mutant DNMT3A upregulates the expression levels of Meis1 even more and maintains cells in an undifferentiated state. These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy.

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