title: Suppression of leukemia development caused by PTEN loss.
abstract: 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.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Schubbert
authors.forename: James Y
authors.initials: JY
authors.lastname: Chen
authors.forename: Bahram
authors.initials: B
authors.lastname: Valamehr
authors.forename: Sherly
authors.initials: S
authors.lastname: Mosessian
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.forename: Nhi H
authors.initials: NH
authors.lastname: Dang
authors.forename: Consuelo
authors.initials: C
authors.lastname: Garcia
authors.forename: Mariana F
authors.initials: MF
authors.lastname: Theodoro
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D018398:Homeodomain Proteins; D007135:Immunoglobulin Variable Region; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; C064658:RAG-1 protein; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus