The Role of Alk in Anaplastic Large-cell Lymphoma (ALCL)
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The Role of Alk in The Role of Alk in Anaplastic Large-cell Anaplastic Large-cell Lymphoma (ALCL)Lymphoma (ALCL)
Andreas StaeblerAndreas Staebler
ALCLALCL
Non-Hodgkin LymphomaNon-Hodgkin Lymphoma
T-cell phenotype predominatesT-cell phenotype predominates
Diverse cellular morphologyDiverse cellular morphology
Seen in children and young adultsSeen in children and young adults
2-8% of all lymphomas 2-8% of all lymphomas ALK translocation in 84% ALK translocation in 84%
Tilley et. al Blood. 1997 Nov 1;90(9):3727-34
Normal ALKNormal ALK
What is it?What is it? RTK RTK
Normal Expression?Normal Expression? Nervous System, Nervous System, gut, and testes.gut, and testes.
Function?Function? Neuronal development and Neuronal development and maintenancemaintenance
www.infobiogen.fr/services/chromcancer/Genes/ALK.html
A Brief Review of RTK functionA Brief Review of RTK function
Recall that RTKs are PM receptorsRecall that RTKs are PM receptors
Upon ligand binding RTKs dimerize Upon ligand binding RTKs dimerize
RTK dimers autophosporilateRTK dimers autophosporilate
Results in activation and initiation of Results in activation and initiation of downstream pathwaysdownstream pathways
Ligand binding activates RTKs by dimerization
Lodish et al. Fig. 20-21
KnockoutsKnockouts
There is There is NONO published literature on ALK published literature on ALK knockout miceknockout mice
Function of ALK demonstrated through Function of ALK demonstrated through 1)In situ hybridization 1)In situ hybridization 2)Overexpression 2)Overexpression
Results Results 1) Expressed in nervous system 1) Expressed in nervous system 2) Activated ALK leads to 2) Activated ALK leads to slow tumorgenesisslow tumorgenesis
Freeman, Matthew. Nature 425, 468 - 469
ALK in DrosophilaALK in Drosophila
Jellybelly (Jeb) is the ligand for ALKJellybelly (Jeb) is the ligand for ALK
Jeb binds to ALK, ALK then activates MAPKJeb binds to ALK, ALK then activates MAPK
This stimulates visceral muscle developmentThis stimulates visceral muscle development
Freeman, Matthew. Nature 425, 468 - 469
ALK mutation in ACLCALK mutation in ACLC
Translocation t(2;5)(p23;q35)Translocation t(2;5)(p23;q35)Fusion protein Fusion protein ALK/NMR (p80)ALK/NMR (p80)
Evident in 84% of all ALCL casesEvident in 84% of all ALCL cases
A chimeric oncogenic version of the trk RTKwas isolated from a human colon carcinoma
Tropomyosin dimerization dimerizes the receptoreven in the absence of ligand
Lodish et al. Fig. 24-16
ALK/NPM Implications in ALCLALK/NPM Implications in ALCL
1997 unregulated ALK activity linked to ALCL1997 unregulated ALK activity linked to ALCLMice expressing activated ALK showed slow Mice expressing activated ALK showed slow tumor genesistumor genesis
Not all mice developed tumorsNot all mice developed tumors
ALK is thought to play an indirect role in ALK is thought to play an indirect role in tumor genesistumor genesis
NPM/ALK PathwaysNPM/ALK Pathways
Imunohistochemical StainingImunohistochemical StainingShowing ALK ExpressionShowing ALK Expression
ALK not normally expressed in LymphocytesALK not normally expressed in Lymphocytes
ALCL TreatmentsALCL Treatments
Currently no ALKCurrently no ALK++ specific treatments specific treatments
Traditional radiation and chemotherapyTraditional radiation and chemotherapy
ALKALK++ ALCL has a better prognosis than ALCL has a better prognosis than ALKALK-- ALCL (5yr. Mean survival). ALCL (5yr. Mean survival).
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