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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

ALK and ALCL

Stephanie Mazzucca

April 5, 2007

anaplastic lymphoma kinase
Anaplastic Lymphoma Kinase
  • Type 1 transmembrane glycoprotein in insulin-RTK superfamily
  • Chromosome 2p23
  • 205 kDa
finding alk
Finding ALK
  • Discovered in 1994
  • Translocation fusion protein found in 1/3 of Anaplastic Large-Cell Lymphomas
finding alk4
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
alk npm fusion
ALK-NPM fusion

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

fish detection
FISH detection

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

targets of alk npm
Targets of ALK/NPM

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

normal functions
Normal Functions
  • No murine model 
normal functions10
Normal Functions
  • No murine model 
  • Drosophila homolog
    • Gut development
    • Retinal Axon Targeting

Dr. Peifer’s Road to Ras ppt

gut development
Gut Development
  • Alk receptor in visceral mesoderm
  • Ligand Jelly belly (Jeb)
  • Mesoderm migration & differentiation
gut development12
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

we still have to remember that
We still have to remember that?

Dr. Peifer’s Road to Ras ppt

  • R1-R8 photoreceptors per ommatidium
  • 800 ommatidia per retina
retinal axon targeting
Retinal Axon Targeting
  • Jeb on photoreceptor axons
  • ALK on target neurons

http://www.nimr.mrc.ac.uk/molneurobiol/salecker/

anaplastic large cell lymphoma alcl
Anaplastic Large-Cell Lymphoma (ALCL)
  • T-cell non-Hodgkin’s lymphoma
    • systemic (lymph nodes)
    • cutaneous (skin nodules)
  • Diagnosed by CD30 surface antigen
alk alcl
ALK+ ALCL
  • First 3 decades of life
  • Male predominance
  • ~85% survival rate

Pulford, K. et al. Blood; 89(4):1394-1404 1997

treatment options
Treatment Options
  • Chemotherapy, radiation, bone marrow transplant
  • monoclonal Antibody SGN-30 against CD-30
    • Phase II trials
    • Induces tumor cell lysis
summary
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
references
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