alk and alcl
DESCRIPTION
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 PresentationTRANSCRIPT
ALK and ALCL
By Alicia Payne
What is ALK?
ALK stands for Anaplastic Lymphoma Kinase
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
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)
Knockout Mice
(-/-) Homozygote Mutants:
Viable Altered behavior Increased number
of progenitor cells in the hippocampus
Reduced body weight
Bilsland et. Al.
How Does ALK Relate to ALCL?
ALCL Basics ALCL = Anaplastic
Large Cell Lymphoma ALCL is a subset of T-
cell non-Hodgkins Lymphoma
Overview of ALK Mutations
Mainly translocations fusion proteins Fusions promote dimerization which
activates ALK
NPM-ALK Fusion Protein
Oncogene 70-80% of
ALK-positive ALCL
t(2;5)(p23;q35) translocation
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
ALK and CD30 Signaling in ALCL Cells
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
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
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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