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).