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Suppression of leukemia development caused by PTEN loss

机译:抑制PTEN丢失引起的白血病发展

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摘要

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 Tcrα/δ-c-myc translocation and T-ALL development regardless of β-catenin activation. We identify mammalian target of rapamydn (mTOR) as a regulator of β-selection. Rapamycin, an mTOR-specific inhibitor, alters nutrient sensing and blocks T-cell differentiation from CD4~-CD8~- to CD4~+CD8~+, the stage where the Tcrα/δ-c-myc translocation occurs. Long-term rapamycin treatment of preleukemic Pten-null mice prevents Tcrα/δ-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.
机译:已知多种遗传或分子改变与癌症干细胞的形成和癌症的发展有关,因此,针对这种改变可能会导致癌症的预防。通过将我们先前建立的磷酸酶和肌腱同源蛋白(Pten)-无效的急性T淋巴细胞白血病(T-ALL)模型与重组激活基因1〜(-/-)背景进行比较,我们发现缺乏可变性,多样性和加入[V(D)J]重组完全消除了Tcrα/δ-c-myc易位和T-ALL发育,无论β-catenin活化如何。我们确定了rapamydn(mTOR)的哺乳动物目标作为β选择的调节器。雷帕霉素是一种mTOR特异性抑制剂,可改变营养成分并阻止T细胞从CD4〜-CD8〜-到CD4〜+ CD8〜+的分化,Tcrα/δ-c-myc发生在此阶段。雷帕霉素对白血病前Pten-null小鼠的长期治疗可防止Tcrα/δ-c-myc易位和白血病干细胞(LSC)的形成,并阻止T-ALL的发展。但是,雷帕霉素本身不能抑制c-Kit中的mTOR信号传导〜(中)CD3〜+ Lin〜-富集了LSCs,并消除了这些细胞。我们的结果支持这样的想法,即防止LSC形成和选择性靶向LSC是抗白血病治疗的有前途的方法。

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  • 作者单位

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

    Department of Medicine, Medical Oncology Division,University of Colorado Cancer Center, University of Colorado Health Sciences Center, Aurora, CO 80262;

    Department of Medicine, Medical Oncology Division,University of Colorado Cancer Center, University of Colorado Health Sciences Center, Aurora, CO 80262;

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, CA 90095,Institute for Molecular Medicine, University of California, Los Angeles, CA 90095;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    genetically engineered animal model; cancer stem cells; targeted therapy;

    机译:基因工程动物模型;癌症干细胞;靶向治疗;

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