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ALK and ALCL. By Alicia Payne. What is ALK?. ALK stands for A naplastic L ymphoma K inase Transmembrane RTK. Pathways Involved with ALK. ALK and Ras-ERK Pathway. ALK and PI3K Pathway. ALK and STAT Pathway. ALK and the Ras-ERK Pathway. ALK in the Cell. - PowerPoint PPT Presentation


  • ALK and ALCLBy Alicia Payne

  • What is ALK?ALK stands for Anaplastic Lymphoma KinaseTransmembrane RTK

  • Pathways Involved with ALKALK and Ras-ERK PathwayALK and PI3K PathwayALK and STAT Pathway

  • ALK and the Ras-ERK Pathway

  • ALK in the CellALK is an RTK involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migrationPossible ligands include Pleiotrophin (PTN) and midkine (MK)

  • Knockout Mice(-/-) Homozygote Mutants:ViableAltered behaviorIncreased number of progenitor cells in the hippocampusReduced body weightBilsland et. Al.

  • How Does ALK Relate to ALCL?

  • ALCL BasicsALCL = Anaplastic Large Cell LymphomaALCL is a subset of T-cell non-Hodgkins Lymphoma

  • Overview of ALK MutationsMainly translocations fusion proteinsFusions promote dimerization which activates ALK

  • NPM-ALK Fusion ProteinOncogene70-80% of ALK-positive ALCLt(2;5)(p23;q35) translocation

  • ALK and ALCLALK fusions increase cell migration rate and cause cytoskeletal rearrangements of lymphoid cellsThis creates anaplastic cells or sheets in the lymph nodes

  • ALK and CD30 Signaling in ALCL Cells

  • TherapyALK-targeted therapy is promising because:Can use CD30-Agonist Antibodies (in ALCL)ALK is not widely expressed; few toxic effectsALCL is mainly a childhood disease; search for effective long-term treatments

  • SummaryALKRTKMainly involved in nervous system develomentActive in lymphoid cells where it is associated with ALCLNPM-ALK Fusion ProteinMain ALK mutationTranslocationPromotes ALK dimerization and activationHyperactivation of ALK promotes cell proliferation, cell survival, migration, and cytoskeletal rearrangements cancerALCLSubset of T-cell NHLALK mutations cause cell migration and cytoskeletal rearrangements of lymphoid cells anaplastic cells or sheets in the lymph nodesALK increases CD30 expression on T-cell tumor cell membranesHowever, even though there is more CD30, it cannot activate the NFKB pathways, and cell-cycle arrest and apoptosis do not occur

  • ReferencesChiarle, Roberto, Voena, Claudia. The anaplastic lymphoma kinase in the pathogenesis of cancerNature Reviews Cancer 2008 8: 11-23Kutok, Jeffery L., Aster, Jon C. Molecular Biology of Anaplastic Lymphoma Kinase-Positive Anaplastic Large-Cell Lymphoma J Clin Oncol 2002 20: 3691-3702 Bilsland, James G., Wheeldon, Alan. Behavioral and Neurochemical Alterations in Mice Deficient in Anaplastic Lymphoma Kinase Suggest Therapeutic Potential for Psychiatric IndicationsNeuropsychopharmacology 2008 33: 685-700

  • References