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ALK and ALCL

ALK and ALCL. By Alicia Payne. What is ALK?. ALK stands for A naplastic L ymphoma K inase Transmembrane RTK. Pathways Involved with ALK. ALK and Ras-ERK Pathway. ALK and PI3K Pathway. ALK and STAT Pathway. ALK and the Ras-ERK Pathway. ALK in the Cell.

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ALK and ALCL

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  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 • 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 • 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

  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 LymphomaJ 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/nature07261-f1.0.jpg&imgrefurl=http://www.nature.com/nature/journal/v455/n7215/full/nature07261.html&usg=__PzotpzazZYwJiyGYW0EtJudfLs8=&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_ENUS274%26sa%3DN%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=15&um=1&tbnid=VnZLq_s5phJB9M:&tbnh=126&tbnw=112&prev=/images%3Fq%3DALK%2Bligand%26hl%3Den%26rlz%3D1G1GGLQ_ENUS274%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=__jjQoa9lKjXvoVNxCNAoW8YY_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%3D20%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://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_enUS233US238%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_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_mym0IbEZ-m1rFQ13RQ=&h=91&w=150&sz=4&hl=en&start=2&um=1&tbnid=acUEGQq4N9tRvM:&tbnh=58&tbnw=96&prev=/images%3Fq%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=hZuMztjBC1zbyM:&tbnh=86&tbnw=115&prev=/images%3Fq%3DALCL%2Btumor%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%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&prev=/images%3Fq%3DALK%2BCD30%2BPathway%26hl%3Den%26rlz%3D1T4ADBS_enUS233US238%26sa%3DN%26um%3D1

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