1. ALK and ALCL By Alicia Payne

2. What is ALK? ALK stands for Anaplastic Lymphoma Kinase Transmembrane RTK

3. Pathways Involved with ALK ALK and Ras-ERK Pathway ALK and PI3K Pathway ALK and STAT Pathway

4. ALK and the Ras-ERK Pathway

5. ALK in the Cell ALK is an RTK involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration Possible ligands include Pleiotrophin (PTN) and midkine (MK)

6. Knockout Mice (-/-) Homozygote Mutants: Viable Altered behavior Increased number of progenitor cells in the hippocampus Reduced body weight Bilsland et. Al.

7. How Does ALK Relate to ALCL?

8. ALCL Basics ALCL = Anaplastic Large Cell Lymphoma ALCL is a subset of T-cell non-Hodgkins Lymphoma

9. Overview of ALK Mutations Mainly translocations  fusion proteins Fusions promote dimerization which activates ALK

10. NPM-ALK Fusion Protein Oncogene 70-80% of ALK- positive ALCL t(2;5)(p23;q35) translocation

11. ALK and ALCL ALK fusions increase cell migration rate and cause cytoskeletal rearrangements of lymphoid cells This creates anaplastic cells or sheets in the lymph nodes

12. ALK and CD30 Signaling in ALCL Cells

13. Therapy ALK-targeted therapy is promising because: Can use CD30-Agonist Antibodies (in ALCL) ALK is not widely expressed; few toxic effects ALCL is mainly a childhood disease; search for effective long-term treatments

14. Summary ALK RTK Mainly involved in nervous system develoment Active in lymphoid cells where it is associated with ALCL NPM-ALK Fusion Protein Main ALK mutation Translocation Promotes ALK dimerization and activation Hyperactivation of ALK promotes cell proliferation, cell survival, migration, and cytoskeletal rearrangements  cancer ALCL Subset of T-cell NHL ALK mutations cause cell migration and cytoskeletal rearrangements of lymphoid cells  anaplastic cells or sheets in the lymph nodes ALK increases CD30 expression on T-cell tumor cell membranes However, even though there is more CD30, it cannot activate the NFKB pathways, and cell-cycle arrest and apoptosis do not occur

15. References Chiarle, Roberto, Voena, Claudia. The anaplastic lymphoma kinase in the pathogenesis of cancer Nature Reviews Cancer 2008 8: 11-23 Kutok, Jeffery L., Aster, Jon C. Molecular Biology of Anaplastic Lymphoma Kinase-Positive Anaplastic Large-Cell Lymphoma J Clin Oncol 2002 20: 3691-3702 Bilsland, James G., Wheeldon, Alan. Behavioral and Neurochemical Alterations in Mice Deficient in Anaplastic Lymphoma Kinase Suggest Therapeutic Potential for Psychiatric Indications Neuropsychopharmacology 2008 33: 685-700 http://images.google.com/imgres?imgurl=http://www.nature.com/nature/journal/v455/n7215/images/natur e07261- f1.0.jpg&imgrefurl=http://www.nature.com/nature/journal/v455/n7215/full/nature07261.html&usg=__Pzotp zazZYwJiyGYW0EtJudfLs8=&h=127&w=150&sz=46&hl=en&start=16&um=1&tbnid=vSneJTdY5V2wCM: &tbnh=81&tbnw=96&prev=/images%3Fq%3DALK%2Bdomains%26hl%3Den%26rlz%3D1G1GGLQ_EN US274%26sa%3DN%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nature/journal/v455/n7215/images/natur e07261- f1.0.jpg&imgrefurl=http://www.nature.com/nature/journal/v455/n7215/full/nature07261.html&usg=__Pzotp zazZYwJiyGYW0EtJudfLs8=&h=127&w=150&sz=46&hl=en&start=16&um=1&tbnid=vSneJTdY5V2wCM: &tbnh=81&tbnw=96&prev=/images%3Fq%3DALK%2Bdomains%26hl%3Den%26rlz%3D1G1GGLQ_EN US274%26sa%3DN%26um%3D1 http://images.google.com/imgres?imgurl=http://soul.ucmp.umu.se/ruth/alkfinal1.gif&imgrefurl=http://soul.u cmp.umu.se/ruth/&usg=__0Jskocmy- H1A6LySQkh6dofNa8g=&h=436&w=388&sz=12&hl=en&start=15&um=1&tbnid=VnZLq_s5phJB9M:&tbn h=126&tbnw=112&prev=/images%3Fq%3DALK%2Bligand%26hl%3Den%26rlz%3D1G1GGLQ_ENUS27 4%26um%3D1 http://images.google.com/imgres?imgurl=http://soul.ucmp.umu.se/ruth/alkfinal1.gif&imgrefurl=http://soul.u cmp.umu.se/ruth/&usg=__0Jskocmy- H1A6LySQkh6dofNa8g=&h=436&w=388&sz=12&hl=en&start=15&um=1&tbnid=VnZLq_s5phJB9M:&tbn h=126&tbnw=112&prev=/images%3Fq%3DALK%2Bligand%26hl%3Den%26rlz%3D1G1GGLQ_ENUS27 4%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v2/n5/thumbs/nrc799- f1.jpg&imgrefurl=http://www.nature.com/nrc/journal/v2/n5/full/nrc799.html&usg=__jjQoa9lKjXvoVNxCNAo W8YY_YZg=&h=131&w=150&sz=9&hl=en&start=33&um=1&tbnid=4WV5v- 0QH99rFM:&tbnh=84&tbnw=96&prev=/images%3Fq%3DNPM%2BALK%2Bdimerization%26ndsp%3D2 0%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26sa%3DN%26start%3D20%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v2/n5/thumbs/nrc799- f1.jpg&imgrefurl=http://www.nature.com/nrc/journal/v2/n5/full/nrc799.html&usg=__jjQoa9lKjXvoVNxCNAo W8YY_YZg=&h=131&w=150&sz=9&hl=en&start=33&um=1&tbnid=4WV5v- 0QH99rFM:&tbnh=84&tbnw=96&prev=/images%3Fq%3DNPM%2BALK%2Bdimerization%26ndsp%3D2 0%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26sa%3DN%26start%3D20%26um%3D1

16. References http://images.google.com/imgres?imgurl=http://soul.ucmp.umu.se/ruth/alkfinal1.gif&imgrefurl=http://soul.ucmp.umu.se/ruth/& usg=__0Jskocmy- H1A6LySQkh6dofNa8g=&h=436&w=388&sz=12&hl=en&start=18&um=1&tbnid=VnZLq_s5phJB9M:&tbnh=126&tbnw=112& prev=/images%3Fq%3DNPM%2BALK%2Bdimer%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://soul.ucmp.umu.se/ruth/alkfinal1.gif&imgrefurl=http://soul.ucmp.umu.se/ruth/& usg=__0Jskocmy- H1A6LySQkh6dofNa8g=&h=436&w=388&sz=12&hl=en&start=18&um=1&tbnid=VnZLq_s5phJB9M:&tbnh=126&tbnw=112& prev=/images%3Fq%3DNPM%2BALK%2Bdimer%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.jst.go.jp/pr/announce/20081016/icons/zu2e.gif&imgrefurl=http://www.jst. go.jp/pr/announce/20081016/index_e.html&usg=__Fsbb- KDR4zqaHrWfMEvadIFA0xQ=&h=277&w=485&sz=15&hl=en&start=14&um=1&tbnid=5v- drC4pcakl0M:&tbnh=74&tbnw=129&prev=/images%3Fq%3DALK%2Btranslocation%26hl%3Den%26rlz%3D1T4ADBS_enU S233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.jst.go.jp/pr/announce/20081016/icons/zu2e.gif&imgrefurl=http://www.jst. go.jp/pr/announce/20081016/index_e.html&usg=__Fsbb- KDR4zqaHrWfMEvadIFA0xQ=&h=277&w=485&sz=15&hl=en&start=14&um=1&tbnid=5v- drC4pcakl0M:&tbnh=74&tbnw=129&prev=/images%3Fq%3DALK%2Btranslocation%26hl%3Den%26rlz%3D1T4ADBS_enU S233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/images/nrc2291- f1.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/fig_tab/nrc2291_F1.html&usg=__ZRvK4S_zliQFSqqsmJhgIHT0brs =&h=294&w=705&sz=64&hl=en&start=5&um=1&tbnid=- FkPKMEkOYQO0M:&tbnh=58&tbnw=140&prev=/images%3Fq%3DALK%2Bpathway%26hl%3Den%26rlz%3D1T4ADBS_en US233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/images/nrc2291- f1.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/fig_tab/nrc2291_F1.html&usg=__ZRvK4S_zliQFSqqsmJhgIHT0brs =&h=294&w=705&sz=64&hl=en&start=5&um=1&tbnid=- FkPKMEkOYQO0M:&tbnh=58&tbnw=140&prev=/images%3Fq%3DALK%2Bpathway%26hl%3Den%26rlz%3D1T4ADBS_en US233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/thumbs/nrc2291- f2.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/full/nrc2291.html%3Fmessage%3Dremove&usg=__ywBldaYy_my m0IbEZ- m1rFQ13RQ=&h=91&w=150&sz=4&hl=en&start=2&um=1&tbnid=acUEGQq4N9tRvM:&tbnh=58&tbnw=96&prev=/images%3 Fq%3DALK%2BPathway%2BSHP1%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/thumbs/nrc2291- f2.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/full/nrc2291.html%3Fmessage%3Dremove&usg=__ywBldaYy_my m0IbEZ- m1rFQ13RQ=&h=91&w=150&sz=4&hl=en&start=2&um=1&tbnid=acUEGQq4N9tRvM:&tbnh=58&tbnw=96&prev=/images%3 Fq%3DALK%2BPathway%2BSHP1%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26um%3D1 http://www.lifeethics.org/www.lifeethics.org/uploaded_images/Hematopoietic-Stem-Cells-10-07-779860.JPG http://images.google.com/imgres?imgurl=http://pleiad.umdnj.edu/~dweiss/T- cell/graphics/alcl_t_hi288x216.jpg&imgrefurl=http://pleiad.umdnj.edu/~dweiss/T-cell/T- cell.html&usg=__Gtq8QGzVk8IkQE7ZoZXdPWEAhxc=&h=216&w=288&sz=15&hl=en&start=7&um=1&tbnid=hZuMztjBC1zb yM:&tbnh=86&tbnw=115&prev=/images%3Fq%3DALCL%2Btumor%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%2 6um%3D1 http://images.google.com/imgres?imgurl=http://pleiad.umdnj.edu/~dweiss/T- cell/graphics/alcl_t_hi288x216.jpg&imgrefurl=http://pleiad.umdnj.edu/~dweiss/T-cell/T- cell.html&usg=__Gtq8QGzVk8IkQE7ZoZXdPWEAhxc=&h=216&w=288&sz=15&hl=en&start=7&um=1&tbnid=hZuMztjBC1zb yM:&tbnh=86&tbnw=115&prev=/images%3Fq%3DALCL%2Btumor%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%2 6um%3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/images/nrc2291- f4.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/fig_tab/nrc2291_F4.html&usg=__8xXRt_YZzVx- pQtgNZEUW0UteFM=&h=491&w=655&sz=90&hl=en&start=2&um=1&tbnid=dLy_cgBRLwTlmM:&tbnh=103&tbnw=138&pre v=/images%3Fq%3DALK%2BCD30%2BPathway%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26sa%3DN%26um %3D1 http://images.google.com/imgres?imgurl=http://www.nature.com/nrc/journal/v8/n1/images/nrc2291- f4.jpg&imgrefurl=http://www.nature.com/nrc/journal/v8/n1/fig_tab/nrc2291_F4.html&usg=__8xXRt_YZzVx- pQtgNZEUW0UteFM=&h=491&w=655&sz=90&hl=en&start=2&um=1&tbnid=dLy_cgBRLwTlmM:&tbnh=103&tbnw=138&pre v=/images%3Fq%3DALK%2BCD30%2BPathway%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26sa%3DN%26um %3D1