Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Finlay, David K.; Sinclair, Linda V.; Feijóo, Carmen G.; Waugh, Caryll; Hagenbeek, Thijs J.; Spits, Hergen; Cantrell, Doreen A.

doi:10.1083/jcb1872oia1

Cited by 11 publications

(21 citation statements)

References 49 publications

(93 reference statements)

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“…Of note, a substantial subset of human T cell acute lymphoblastic leukemias are associated with mutations in PTEN (7)(8)(9). This is consistent with a murine model, in which mice with a deletion of Pten targeted to the T cell compartment (using either CD4-Cre or Lck-Cre) uniformly developed T cell lymphomas by 10-16 weeks of age (10)(11)(12)(13).…”

Section: Introductionsupporting

confidence: 62%

“…By crossing these mice with Rag2- and γc-deficient mice, the authors showed that PTEN deficiency can substitute for both IL-7 receptor and pre- TCR signals in the thymus. Higher basal PI3K signals maintained in the absence of PTEN likely promote survival and proliferation of developing thymocytes even in the absence of normally required environmental and cellular cues, bypassing the normal PDK1 checkpoint regulation of cell growth (13).…”

Section: Discussionmentioning

confidence: 99%

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Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

Liu

Karnell²,

Yin³

et al. 2010

J. Clin. Invest.

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Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity.

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Section: Introductionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

Liu

Karnell²,

Yin³

et al. 2010

J. Clin. Invest.

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“…While PDK1 is not the rate limiting factor for the pathway, it is still absolutely required for phosphorylation of AKT T308 as recently shown in using conditional PDK1 knockouts. The total loss of PDK1 in PTEN-deficient context completely abolishes p-AKT T308 and prevents formation of T-Cell leukemia (8,9).…”

Section: Tumor Incidence In Heterozygous Ptenmentioning

confidence: 99%

“…PIP 3 causes PDK1 and AKT to colocalize at the plasma membrane via their pleckstrin homology domains (4,5). Here, PDK1 phosphorylates the kinase T-loop residue AKT T308 , an event that is absent in PDK1 knockout embryonic stem cells (6) and tissuespecific PDK1 ablation mouse models (7)(8)(9). Full activation of AKT also requires phosphorylation of AKT S473 by mTORC2 (10).…”

Section: Introductionmentioning

confidence: 99%

PDK1 Attenuation Fails to Prevent Tumor Formation in PTEN-Deficient Transgenic Mouse Models

et al. 2011

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PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development. However, while PDK1 has been investigated intensively as an oncology target, selective inhibitors suitable for in vivo studies have remained elusive. In this study we present the results of in vivo PDK1 inhibition through a universally applicable RNAi approach for functional drug target validation in oncogenic pathway contexts. This approach, which relies on doxycycline-inducible shRNA expression from the Rosa26 locus, is ideal for functional studies of genes like PDK1 where constitutive mouse models lead to strong developmental phenotypes or embryonic lethality. We achieved more than 90% PDK1 knockdown in vivo, a level sufficient to impact physiological functions resulting in hyperinsulinemia and hyperglycemia. This phenotype was reversible on PDK1 reexpression. Unexpectedly, longterm PDK1 knockdown revealed a lack of potent antitumor efficacy in 3 different mouse models of PTENdeficient cancer. Thus, despite efficient PDK1 knockdown, inhibition of the PI3K pathway was marginal suggesting that PDK1 was not a rate limiting factor. Ex vivo analysis of pharmacological inhibitors revealed that AKT and mTOR inhibitors undergoing clinical development are more effective than PDK1 inhibitors at blocking activated PI3K pathway signaling. Taken together our findings weaken the widely held expectation that PDK1 represents an appealing oncology target. Cancer Res; 71(8); 3052-65. Ó2011 AACR.

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“…AKT activation has been reported to be involved in the regulation of β-selection (20,21,26,27). Among various AKT substrates, mTOR can be activated by AKT, whereas the activated target of rapamycin complex II (TORCII) complex has phosphoinositide-dependent kinase 2 (PDK2) activity and can further activate AKT (28,29).…”

Section: Pten Loss Enablesmentioning

confidence: 99%

Suppression of leukemia development caused by PTEN loss

Guo

Schubbert

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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. T -lymphoblastic leukemia (T-ALL) is a common hematological malignancy that is associated with poor prognosis compared with other ALLs and is often fatal without effective treatment (1). Activating mutations in Notch gene homolog 1 (NOTCH1) are reported in 34-71% of human T-ALL patients (2, 3), whereas deletion or mutations of the phosphatase and tensin homolog (PTEN). tumor suppressor gene have recently been detected in 8-63% of pediatric T-ALL patients (3-6). The mutation status of NOTCH1 and PTEN can divide pediatric T-ALL patients into three groups: (i) those with both NOTCH1 and PTEN mutations, (ii) those with NOTCH1/F-box and WD repeat domain containing 7 (FBXW7) mutations, and (iii) those with only PTEN mutations (3). Interestingly, constitutive activation of the NOTCH signaling pathway is known to down-regulate PTEN expression (5, 7), suggesting that PTEN and its controlled PI3K/v-akt murine thymoma viral oncogene homolog (AKT)/mTOR pathway are critical for the etiology of human T-ALL. Furthermore, PTEN deletion seems to be correlated with poor response to chemotherapy (6) and resistance to pharmacological inhibition of NOTCH1 (5). Therefore, understanding the molecular mechanisms of PTEN-mediated T-ALL pathogenesis and drug resistance is a critical step to improving T-ALL therapeutics.To investigate the molecular and cellular mechanisms associated with PTEN-controlled T-ALL pathogenesis and therapeutic resistance, we have recently developed a Pten loxP/loxP ;VE-CadherinCre + ;Rosa26 loxP-stop-loxP -LacZ + (Pten null) T-ALL mouse model by conditional deletion of Pten in a subset of fetal liver hematopoietic stem cells (8). The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance. Besides Pt...

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Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Cited by 11 publications

References 49 publications

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

PDK1 Attenuation Fails to Prevent Tumor Formation in PTEN-Deficient Transgenic Mouse Models

Suppression of leukemia development caused by PTEN loss

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