1. The Role of Alk in Anaplastic Large-cell Lymphoma (ALCL) Andreas Staebler

2. ALCL Non-Hodgkin Lymphoma T-cell phenotype predominates Diverse cellular morphology Seen in children and young adults 2-8% of all lymphomas ALK translocation in 84% Tilley et. al Blood. 1997 Nov 1;90(9):3727-34

3. Normal ALK What is it? RTK Normal Expression? Nervous System, gut, and testes. Function? Neuronal development and maintenance www.infobiogen.fr/services/chromcancer/Genes/ALK.html

4. A Brief Review of RTK function Recall that RTKs are PM receptors Upon ligand binding RTKs dimerize RTK dimers autophosporilate Results in activation and initiation of downstream pathways

5. Ligand binding activates RTKs by dimerization Lodish et al. Fig. 20-21

6. Knockouts There is NO published literature on ALK knockout mice Function of ALK demonstrated through 1)In situ hybridization 2)Overexpression Results 1) Expressed in nervous system 2) Activated ALK leads to slow tumorgenesis Freeman, Matthew. Nature 425, 468 - 469

7. ALK in Drosophila Jellybelly (Jeb) is the ligand for ALK Jeb binds to ALK, ALK then activates MAPK This stimulates visceral muscle development Freeman, Matthew. Nature 425, 468 - 469

8. ALK mutation in ACLC Translocation t(2;5)(p23;q35) Fusion protein ALK/NMR (p80) Evident in 84% of all ALCL cases

10. A chimeric oncogenic version of the trk RTK was isolated from a human colon carcinoma Tropomyosin dimerization dimerizes the receptor even in the absence of ligand Lodish et al. Fig. 24-16

11. ALK/NPM Implications in ALCL 1997 unregulated ALK activity linked to ALCL Mice expressing activated ALK showed slow tumor genesis Not all mice developed tumors ALK is thought to play an indirect role in tumor genesis

12. NPM/ALK Pathways

13. Imunohistochemical Staining Showing ALK Expression ALK not normally expressed in Lymphocytes

14. ALCL Treatments Currently no ALK + specific treatments Traditional radiation and chemotherapy ALK + ALCL has a better prognosis than ALK - ALCL (5yr. Mean survival).