Advertisement

Molecular Targeted Therapies in T-Cell Acute Lymphoblastic Leukemia

  • Alejandro Gutierrez
  • A. Thomas Look
Chapter

Abstract

T cell precursors arise from hematopoietic progenitors in the bone marrow and migrate to the thymus, where they undergo a series of proliferation and differentiation steps that include the somatic recombination of T cell receptor (TCR) gene loci (Market and Papavasiliou 2003). TCR gene rearrangements are followed by positive and negative selection steps that allow the survival of T cells only if their TCR functions appropriately within the context of an individual’s immune microenvironment. This highly regulated developmental process results in the generation of a population of T cells with a wide range of somatically acquired T cell receptor variation, which forms the foundation of a fully competent adaptive immune system that can respond to a countless variety of foreign antigens. Genetic alterations involving oncogenes or tumor suppressors can result in the aberrant proliferation, differentiation arrest, and clonal expansion of T cell precursors that is characteristic of T cell acute lymphoblastic leukemia (T-ALL)

Keywords

NOTCH1 Signaling Oncogenic Transcription Factor Cell Lymphoblastic Lymphoma Activate NOTCH1 Mutation Negative Selection Step 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Armstrong SA, Look AT (2005) Molecular genetics of acute lymphoblastic leukemia. Journal of Clinical Oncology 23:6306–6315.PubMedCrossRefGoogle Scholar
  2. Bernasconi P et al. (2005) ABL1 amplification in T-cell acute lymphoblastic leukemia. Cancer Genet Cytogenet 162:146–50.PubMedCrossRefGoogle Scholar
  3. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–89.PubMedCrossRefGoogle Scholar
  4. Brugge J et al. (2007) A new mutational AKTivation in the PI3K pathway. Cancer Cell 12:104–7.PubMedCrossRefGoogle Scholar
  5. Cairo MS et al. (2005) Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future. Pediatr Blood Cancer 45:753–69.PubMedCrossRefGoogle Scholar
  6. Chow LM, Baker SJ (2006) PTEN function in normal and neoplastic growth. Cancer Lett 241:184–96.PubMedCrossRefGoogle Scholar
  7. De Keersmaecker K et al. (2005) Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). Blood 105:4849–52.PubMedCrossRefGoogle Scholar
  8. DeAngelo DJ et al. (2006). A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. Abstract, American Society of Clinical Oncology 2006 Annual Meeting.Google Scholar
  9. Ellisen LW et al. (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–61.PubMedCrossRefGoogle Scholar
  10. Ferrando AA et al. (2004) Biallelic transcriptional activation of oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Blood 103:1909–11.PubMedCrossRefGoogle Scholar
  11. Ferrando AA, Look AT (2003) Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin Hematol 40:274–80.PubMedCrossRefGoogle Scholar
  12. Flex E et al. (2008) Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 205:751–8.PubMedCrossRefGoogle Scholar
  13. Gavathiotis E et al. (2008) BAX activation is initiated at a novel interaction site. Nature 455:1076–81.PubMedCrossRefGoogle Scholar
  14. Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–44.PubMedCrossRefGoogle Scholar
  15. Grabher C et al. (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 6:347–59.PubMedCrossRefGoogle Scholar
  16. Graux C et al. (2004) Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 36:1084–9.PubMedCrossRefGoogle Scholar
  17. Guo W et al. (2008) Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453:529–33.PubMedCrossRefGoogle Scholar
  18. Gutierrez A, Look AT (2007) NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 12:411–413.PubMedCrossRefGoogle Scholar
  19. Gutierrez A et al. (2009) High frequency of PTEN, PI3K and AKT abnormalities in T cell acute lymphoblastic leukemia. Blood 114:647–50.PubMedCrossRefGoogle Scholar
  20. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–30.PubMedCrossRefGoogle Scholar
  21. Hopkins AL, Groom CR (2003) Target analysis: a priori assessment of druggability. Ernst Schering Res Found Workshop:11–7.Google Scholar
  22. Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131:965–73.PubMedCrossRefGoogle Scholar
  23. Liang DC et al. (2006) K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer 106:950–6.PubMedCrossRefGoogle Scholar
  24. Maillard I et al. (2006) Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood 107:3511–9.PubMedCrossRefGoogle Scholar
  25. Market E, Papavasiliou FN (2003) V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol 1:E16.PubMedCrossRefGoogle Scholar
  26. Maser RS et al. (2007) Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447:966–71.PubMedCrossRefGoogle Scholar
  27. Milano J et al. (2004) Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82:341–58.PubMedCrossRefGoogle Scholar
  28. Morgan TH (1917) The Theory of the Gene. The American Naturalist 51:513.CrossRefGoogle Scholar
  29. Mullighan CG et al. (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–64.PubMedCrossRefGoogle Scholar
  30. O’Neil J et al. (2007) FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 204:1813–24.PubMedCrossRefGoogle Scholar
  31. Palomero T et al. (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 103:18261–6.PubMedCrossRefGoogle Scholar
  32. Palomero T et al. (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13:1203–10.PubMedCrossRefGoogle Scholar
  33. Perentesis JP et al. (2004) RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia 18:685–92.PubMedCrossRefGoogle Scholar
  34. Quintas-Cardama A et al. (2008) Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia 22:1117–24.PubMedCrossRefGoogle Scholar
  35. Radtke F et al. (2004) Notch regulation of lymphocyte development and function. Nat Immunol 5:247–53.PubMedCrossRefGoogle Scholar
  36. Real PJ et al. (2009) Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 15:50–8.PubMedCrossRefGoogle Scholar
  37. Reinherz EL, Schlossman SF (1980) Current concepts in immunology: Regulation of the immune response--inducer and suppressor T-lymphocyte subsets in human beings. N Engl J Med 303:370–3.PubMedCrossRefGoogle Scholar
  38. Rizzo P et al. (2008) Rational targeting of Notch signaling in cancer. Oncogene 27:5124–31.PubMedCrossRefGoogle Scholar
  39. Rothenberg EV, Taghon T (2005) Molecular genetics of T cell development. Annu Rev Immunol 23:601–49.PubMedCrossRefGoogle Scholar
  40. Russ AP, Lampel S (2005) The druggable genome: an update. Drug Discov Today 10:1607–10.PubMedCrossRefGoogle Scholar
  41. Scholl C et al. (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137:821–34.PubMedCrossRefGoogle Scholar
  42. Schubbert S et al. (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308.PubMedCrossRefGoogle Scholar
  43. Sharma VM et al. (2006) Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 26:8022–31.PubMedCrossRefGoogle Scholar
  44. Sirvent A et al. (2008) Cytoplasmic signalling by the c-Abl tyrosine kinase in normal and cancer cells. Biol Cell 100:617–31.PubMedCrossRefGoogle Scholar
  45. Staal FJ et al. (2001) Transcriptional control of T-lymphocyte differentiation. Stem Cells 19:165–79.PubMedCrossRefGoogle Scholar
  46. Thompson BJ et al. (2007) The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 204:1825–35.PubMedCrossRefGoogle Scholar
  47. van Es JH et al. (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–63.PubMedCrossRefGoogle Scholar
  48. Verdine GL, Walensky LD (2007) The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res 13:7264–70.PubMedCrossRefGoogle Scholar
  49. Walensky LD et al. (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466–70.PubMedCrossRefGoogle Scholar
  50. Wei G et al. (2006) Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10:331–42.PubMedCrossRefGoogle Scholar
  51. Weng AP et al. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–71.PubMedCrossRefGoogle Scholar
  52. Weng AP et al. (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–109.PubMedCrossRefGoogle Scholar
  53. Wong GT et al. (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876–82.PubMedCrossRefGoogle Scholar
  54. Yilmaz OH et al. (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–82.PubMedCrossRefGoogle Scholar
  55. Zweidler-McKay PA, Pear WS (2004) Notch and T cell malignancy. Semin Cancer Biol 14:329–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pediatric OncologyDana-Farber Cancer Institute and Children’s Hospital BostonBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA

Personalised recommendations