ALK and ALCL
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Transcript of ALK and ALCL
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ALK and ALCL
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 and ALCL
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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Therapy
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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SummaryALK
•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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References http://images.google.com/imgres?imgurl=http://soul.ucmp.umu.se/ruth/alkfinal1.gif&imgrefurl=http://soul.ucmp.umu.se/ruth/
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