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ALK and ALCL By Alicia Payne

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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. - PowerPoint PPT Presentation

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Page 1: ALK and ALCL

ALK and ALCL

By Alicia Payne

Page 2: ALK and ALCL

What is ALK?

ALK stands for Anaplastic Lymphoma Kinase

Transmembrane RTK

Page 3: ALK and ALCL

Pathways Involved with ALK

ALK and Ras-ERK Pathway

ALK and PI3K Pathway

ALK and STAT Pathway

Page 4: ALK and ALCL

ALK and the Ras-ERK Pathway

Page 5: ALK and ALCL

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)

Page 6: ALK and ALCL

Knockout Mice

(-/-) Homozygote Mutants:

Viable Altered behavior Increased number

of progenitor cells in the hippocampus

Reduced body weight

Bilsland et. Al.

Page 7: ALK and ALCL

How Does ALK Relate to ALCL?

Page 8: ALK and ALCL

ALCL Basics ALCL = Anaplastic

Large Cell Lymphoma ALCL is a subset of T-

cell non-Hodgkins Lymphoma

Page 9: ALK and ALCL

Overview of ALK Mutations

Mainly translocations fusion proteins Fusions promote dimerization which

activates ALK

Page 10: ALK and ALCL

NPM-ALK Fusion Protein

Oncogene 70-80% of

ALK-positive ALCL

t(2;5)(p23;q35) translocation

Page 11: ALK and ALCL

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

Page 12: ALK and ALCL

ALK and CD30 Signaling in ALCL Cells

Page 13: ALK and ALCL

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

Page 14: ALK and ALCL

SummaryALK

•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

Page 15: ALK and ALCL

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 IndicationsNeuropsychopharmacology 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

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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