Proapoptotic BID is required for myeloid homeostasis and tumor suppression

被引:138
作者
Zinkel, SS
Ong, CC
Ferguson, DO
Iwasaki, H
Akashi, K
Bronson, RT
Kutok, JL
Alt, FW
Korsmeyer, SJ [1 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol,Howard Hughes Med Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med,Howard Hughes Med Inst, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med,Dept Genet, Howard Hughes Med Inst,Ctr Blood Res, Div Immunol,Boston Childrens Hosp, Boston, MA 02115 USA
关键词
BID; BCL-2; myeloid; cancer; apoptosis; Fas;
D O I
10.1101/gad.1045603
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a "BH3-only" molecule, amplifies death receptor signals connecting the extrinsic to intrinsic pathways by triggering the mitochondrial pathway of apoptosis. Bid-deficient mice, as they age, spontaneously develop a myeloproliferative disorder, which progresses from myeloid hyperplasia to a fatal, clonal malignancy closely resembling chronic myelomonocytic leukemia (CMML). Thus, an apoptotic defect can result in myeloid leukemogenesis. Premalignant Bid-/- myeloid precursor cells are resistant to death receptor-induced apoptosis. Furthermore, a competitive reconstitution assay demonstrates that Bid-deficient long-term repopulating cells give rise to expanded myelomortocytic cells in vivo. Surprisingly, a single BH3-only molecule operating in the extrinsic death receptor pathway proved essential in vivo for physiologic cell death required to maintain myeloid homeostasis. Moreover, progression to CMML indicates that an upstream BH3-only molecule, BID, is required to suppress tumorigenesis.
引用
收藏
页码:229 / 239
页数:11
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