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ALK and ALCL By Alicia Payne

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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


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By Alicia Payne

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What is ALK?

ALK stands for Anaplastic Lymphoma Kinase

Transmembrane RTK

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Pathways Involved with ALK

ALK and Ras-ERK Pathway

ALK and PI3K Pathway

ALK and STAT Pathway

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ALK and the Ras-ERK Pathway

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ALK in the Cell

ALK is an RTK involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration

Possible ligands include Pleiotrophin (PTN) and midkine (MK)

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Knockout Mice

(-/-) Homozygote Mutants:

Viable Altered behavior Increased number

of progenitor cells in the hippocampus

Reduced body weight

Bilsland et. Al.

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How Does ALK Relate to ALCL?

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ALCL Basics ALCL = Anaplastic

Large Cell Lymphoma ALCL is a subset of T-

cell non-Hodgkins Lymphoma

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Overview of ALK Mutations

Mainly translocations fusion proteins Fusions promote dimerization which

activates ALK

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NPM-ALK Fusion Protein

Oncogene 70-80% of

ALK-positive ALCL

t(2;5)(p23;q35) translocation

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ALK fusions increase cell migration rate and cause cytoskeletal rearrangements of lymphoid cells

This creates anaplastic cells or sheets in the lymph nodes

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ALK and CD30 Signaling in ALCL Cells

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ALK-targeted therapy is promising because:

Can use CD30-Agonist Antibodies (in ALCL)

ALK is not widely expressed; few toxic effects

ALCL is mainly a childhood disease; search for effective long-term treatments

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•RTK•Mainly involved in nervous system develoment•Active in lymphoid cells where it is associated with ALCL

NPM-ALK Fusion Protein

•Main ALK mutation•Translocation•Promotes ALK dimerization and activation•Hyperactivation of ALK promotes cell proliferation, cell survival, migration, and cytoskeletal rearrangements cancer

ALCL•Subset of T-cell NHL•ALK mutations cause cell migration and cytoskeletal rearrangements of lymphoid cells anaplastic cells or sheets in the lymph nodes•ALK increases CD30 expression on T-cell tumor cell membranes•However, even though there is more CD30, it cannot activate the NFKB pathways, and cell-cycle arrest and apoptosis do not occur

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References Chiarle, Roberto, Voena, Claudia. The anaplastic lymphoma kinase in the pathogenesis of cancer

Nature Reviews Cancer 2008 8: 11-23 Kutok, Jeffery L., Aster, Jon C.

Molecular Biology of Anaplastic Lymphoma Kinase-Positive Anaplastic Large-Cell LymphomaJ 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

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