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Suppression of leukemia development caused by PTEN loss.

Proceedings of the National Academy of Sciences of the United States of America | January 25, 2011 |

Guo, Wei | Schubbert, Suzanne | Chen, James Y | Valamehr, Bahram | Mosessian, Sherly | Shi, Hubing | Dang, Nhi H | Garcia, Consuelo | Theodoro, Mariana F | Varella-Garcia, Marileila | Wu, Hong
Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Abstract

Multiple genetic or molecular alterations are known to be associated with cancer stem cell formation and cancer development. Targeting such alterations ... cells. Our results support the idea that preventing LSC formation and selectively targeting LSCs are promising approaches for antileukemia therapies.

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 rapamycin (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.

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Pnas.1006937108fig01
Fig 1. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.
Pnas.1006937108fig01
Fig 1. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Fig 1

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Pnas.1006937108fig02
Fig 2. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.
Pnas.1006937108fig02
Fig 2. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Fig 2

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Pnas.1006937108fig03
Fig 3. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.
Pnas.1006937108fig03
Fig 3. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Fig 3

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Pnas.1006937108fig04
Fig 4. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.
Pnas.1006937108fig04
Fig 4. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Fig 4

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Pnas.1006937108fig05
Fig 5. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.
Pnas.1006937108fig05
Fig 5. Guo, Schubbert, et al. "Suppression of leukemia development caused by PTEN loss." Proceedings of the National Academy of Sciences of the United States of America 108.4 (2011): 1409-14. Web.

Fig 5

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