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ALK and ALCL

ALK and ALCL . Stephanie Mazzucca April 5, 2007. Anaplastic Lymphoma Kinase . Type 1 transmembrane glycoprotein in insulin-RTK superfamily Chromosome 2p23 205 kDa . Finding ALK. Discovered in 1994 Translocation fusion protein found in 1/3 of Anaplastic Large-Cell Lymphomas. Finding ALK.

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ALK and ALCL

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  1. ALK and ALCL Stephanie Mazzucca April 5, 2007

  2. Anaplastic Lymphoma Kinase • Type 1 transmembrane glycoprotein in insulin-RTK superfamily • Chromosome 2p23 • 205 kDa

  3. Finding ALK • Discovered in 1994 • Translocation fusion protein found in 1/3 of Anaplastic Large-Cell Lymphomas

  4. Finding ALK • Discovered in 1994 • Translocation fusion protein found in 1/3 of Anaplastic Large-Cell Lymphomas • Fused with nucleophosmin (NPM) • Shuttles proteins from nucleolus to cytoplasm for ribosome assembly • Ubiquitously expressed from a strong promoter

  5. ALK-NPM fusion Kutok, J. L. et al. J Clin Oncol; 20:3691-3702 2002

  6. FISH detection Kutok, J. L. et al. J Clin Oncol; 20:3691-3702 2002

  7. Targets of ALK/NPM Kutok, J. L. et al. J Clin Oncol; 20:3691-3702 2002

  8. What is ALK’s normal job?

  9. Normal Functions • No murine model 

  10. Normal Functions • No murine model  • Drosophila homolog • Gut development • Retinal Axon Targeting Dr. Peifer’s Road to Ras ppt

  11. Gut Development • Alk receptor in visceral mesoderm • Ligand Jelly belly (Jeb) • Mesoderm migration & differentiation

  12. Gut Development • Alk receptor in visceral mesoderm • Ligand Jelly belly (Jeb) • Mesoderm migration & differentiation Lorén C. et al. EMBO reports; 4(8): 781-786 2003

  13. We still have to remember that? Dr. Peifer’s Road to Ras ppt • R1-R8 photoreceptors per ommatidium • 800 ommatidia per retina

  14. Retinal Axon Targeting • Jeb on photoreceptor axons • ALK on target neurons http://www.nimr.mrc.ac.uk/molneurobiol/salecker/

  15. What kind of cancer does ALK cause?

  16. Anaplastic Large-Cell Lymphoma (ALCL) • T-cell non-Hodgkin’s lymphoma • systemic (lymph nodes) • cutaneous (skin nodules) • Diagnosed by CD30 surface antigen

  17. ALK+ ALCL • First 3 decades of life • Male predominance • ~85% survival rate Pulford, K. et al. Blood; 89(4):1394-1404 1997

  18. Treatment Options • Chemotherapy, radiation, bone marrow transplant • monoclonal Antibody SGN-30 against CD-30 • Phase II trials • Induces tumor cell lysis

  19. Summary • RTK for signal transduction • In Drosophila, involved in gut development and connecting retina to brain • When fused with NPM, overexpression leads to uncontrolled proliferation of lymphoid cells

  20. Questions?

  21. References • Bazigou E. et al. (2007). Anterograde Jelly belly and Alk Receptor Tyrosine Kinase Signaling Mediates Axon Targeting in Drosophila. Cell. 128, 961-975. • Kutok J.L. (2002). Molecular Biology of Anaplastic Lymphoma Kinase-Positive Anaplastic Large-Cell Lymphoma. J Clin Onc. 20, 3691-3702 • Lorén C. et al. (2003) A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster. EMBO Reports. 4, 781-786. • Morris S.W. (1994). Fusion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma. Science, 263. 1281-1284. • Pulford K. et al. (1997) Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood, 89. 1394-1404. • http://www.nimr.mrc.ac.uk/molneurobiol/salecker/ • http://www.alcl.com/systemic_contributions.html

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