期刊
NATURE MEDICINE
卷 22, 期 4, 页码 379-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4062
关键词
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资金
- US National Institutes of Health (NIH)
- National Cancer Institute [R01CA137060, R01CA139032, R01CA157644, R01CA169458, R01CA172558]
- William Lawrence and Blanche Hughes Foundation
- California Institute for Regenerative Medicine (CIRM) [TR2-01816]
- Bloodwise
- Research Scholar Award from the American Cancer Society [RSG-12-257-01-TBE]
- Established Investigator Award from the Melanoma Research Alliance [20120279]
- NIH-National Center for Advancing Translational Science (NCATS) UCLA CTSI grant [UL1TR000124]
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.
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