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Molecular Targets in T-ALL: Translating Posttranslational Alterations into Therapy?

This article explores the potential of targeting intracellular alterations and extracellular factors in T-ALL (acute lymphoblastic leukemia) as a novel therapeutic approach. Specifically, it focuses on the PI3K/Akt pathway and PTEN alterations as potential therapeutic targets.

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Molecular Targets in T-ALL: Translating Posttranslational Alterations into Therapy?

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  1. New molecular therapeutical targets - in leukemia T-ALL signals: translating posttranslational alterations into therapy? João T. Barata Instituto de Medicina Molecular, Lisboa, Portugal

  2. Extracellular Factors Cancer Progression Intracellular Alterations

  3. Extracellular Factors Signal Transduction Pathways Cancer Progression Intracellular Alterations

  4. Extracellular Factors Signal Transduction Pathways T-ALL Progression Intracellular Alterations

  5. Acute Lymphoblastic Leukemia (ALL) • The most frequent childhood malignancy • Malignant clones originate from T or B cell progenitors • arrested at different stages of lymphoid development T-Cell Acute Lymphoblastic Leukemia (T-ALL) • Worse prognosis than B-lineage ALL patients • The use multi-agent chemotherapy • has significantly improved treatment outcome • Roughly 20% of the patients relapse and have a dismal prognosis Novel, more selective, less detrimental therapies are required

  6. Extracellular Factors Signal Transduction Pathways T-ALL Progression Intracellular Alterations

  7. PI3K PTEN Proliferation Viability Migration Growth Akt/ PKB PIP2 PIP3 PI3K/Akt(PKB) pathway – hyperactivated in human cancer PTEN – frequently inactivated in human cancer:  genetic lesions / epigenetic alterations  diminished/absent mRNA and protein

  8. Is PI3K/Akt(PKB) pathway constitutively hyperactivated in primary T-ALL cells?

  9. PI3K/Akt signaling pathway constitutive hyperactivation in primary T-ALL cells Most primary T-ALLs (87.5% - 21/24) display PI3K/Akt pathway hyperactivation Silva et al, JCI 2008, 118:3762

  10. PI3K PTEN  Which mechanisms lead to PI3K/Akt pathway hyperactivation in T-ALL? Akt/ PKB PIP2 PIP3

  11. PTEN mutations and protein expression alterations 80% of the cases express PTEN.

  12. Increased PTEN expression associates with decreased activity and increased phosphorylation

  13. CK2 P PTEN P P PTEN Phosphatase Active Inactive Degradation Stabilization Vazquez et al, MCB 2000, 20:5010; Torres & Pulido 2001, JBC 276:993; Miller et al, FEBS Lett 528:145

  14. PTEN expression and activity are regulated by CK2 in PTEN+ T-ALL cells

  15.  Are primary T-ALL cells dependent on these mechanisms for their survival?

  16. Inhibition of PI3K or CK2 promotes cell death selectively in T-ALL cells

  17. Silva et al, JCI 2008, 118:3762

  18. Cell Growth Cell Cycle Viability T-ALL 72% patients IL-7 PI3K / Akt (PKB) TfR Glut1 Glucose uptake p27kip1 Mitochondrial homeostasis pRb hyper-P Bcl-2 Barata et al. Blood 2001, 98:1524; Haematologica 2004, 89:1459; Blood 2004, 103:1891; J Exp Med 2004, 200:659

  19. Does IL-7 contribute to leukemia progression in vivo?

  20. Human T-ALL cells Human T-ALL cells mIL-7 mIL-7 vs Rag2-/- Il2rg-/- (IL-7 WT) Rag2-/- Il2rg-/-Il7-/- (IL-7 KO)

  21. IL-7 accelerates leukemia expansion in mice xenotransplanted with T-ALL cell lines HPB-ALL-luc-eGFP Silva et al, unpublished

  22. IL-7 accelerates leukemia expansion in mice xenotransplanted with human primary T-ALL cells

  23. IL-7 promotes p27Kip1 downregulation, Bcl-2 upregulation, proliferation and viability of xenotransplanted human primary T-ALL cells Silva et al, unpublished

  24. Ex vivo evidence for leukemia cell responsiveness to IL-7 in T-ALL patients IL-7 IL7RA Park et al, Immunity 2004, 21:289 IL-7- IL-7R IL-7 (consumption) Guimond et al, Nat Immunol 2009, 10:149

  25. IL-7 contributes to human T-ALL in vivo

  26. Extracellular Factors Signal Transduction Pathways T-ALL Progression Intracellular Lesions

  27. a-IL-7; a-IL-7Ra Abs; Pharmacological inhibitors IL-7 PI3K/Akt inhibitors T-ALL Progression PI3K/Akt CK2 inhibitors (CX-4945) CK2

  28. Cancer Biology Unit (IMM) Ana Silva Bruno Cardoso Leila Martins National Institute for Medical Research, London, UK Ben Seddon Centro InfantilBoldrini, SP, Brazil J. Andrés Yunes Patricia Jotta Angelo Laranjeira Hospital de Santa Cruz, Portugal Miguel Abecasis University of Dundee, UK Nick Leslie Fundaçãopara a Ciência e a Tecnologia FundaçãoCalousteGulbenkian Associação Portuguesa Contra a Leucemia Children with Leukaemia, UK LPC/NRS – Terry Fox

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