期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 4, 页码 1409-1414出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006937108
关键词
genetically engineered animal model; cancer stem cells; targeted therapy
资金
- California Institute of Regenerative Medicine
- Leukemia and Lymphoma Society
- University of California Los Angeles
Multiple genetic or molecular alterations are known to be associated with cancer stem cell formation and cancer development. Targeting such alterations, therefore, may lead to cancer prevention. By crossing our previously established phosphatase and tensin homolog (Pten)-null acute T-lymphoblastic leukemia (T-ALL) model onto the recombination-activating gene 1(-/-) background, we show that the lack of variable, diversity and joining [V(D)J] recombination completely abolishes the Tcr alpha/delta-c-myc translocation and T-ALL development, regardless of beta-catenin activation. We identify mammalian target of rapamycin (mTOR) as a regulator of beta-selection. Rapamycin, an mTOR-specific inhibitor, alters nutrient sensing and blocks T-cell differentiation from CD4(-)CD8(-) to CD4(+)CD8(+), the stage where the Tcr alpha/delta-c-myc translocation occurs. Long-term rapamycin treatment of preleukemic Pten-null mice prevents Tcr alpha/delta-c-myc translocation and leukemia stem cell (LSC) formation, and it halts T-ALL development. However, rapamycin alone fails to inhibit mTOR signaling in the c-Kit(mid)CD3(+)Lin(-) population enriched for LSCs and eliminate these cells. Our results support the idea that preventing LSC formation and selectively targeting LSCs are promising approaches for antileukemia therapies.
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