title: ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group.
abstract: BACKGROUND
  ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway-associated factors in pediatric cases and cell lines.
  
  
  METHODS
  Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25). Slides were examined by immunohistochemistry for phospho(p)-Akt and PTEN, the primary feedback regulator of the pathway, as well as for p27kip1 and stathmin-1. ALCL cell lines SUDHL-1 and Karpas-299 were examined for ALK, pALK, pAkt, p27/Kip1, PTEN, pPTEN, CD30, pSTAT3, and pSTAT5; ALK inhibition was performed using compound PF-2341066 and PTEN genes were sequenced.
  
  
  RESULTS
  A majority of patients expressed pAkt, PTEN, and stathmin, with p27kip1 levels less than controls. Cell lines showed expression of ALK, pALK, pSTAT3, pSTAT5, CD30, pAkt, PTEN, and pPTEN, with p27 slightly less than positive controls, and germline PTEN DNA. There was evidence of phosphorylated PTEN (pPTEN) associated with inhibited function. Pharmacologic inhibition of activated ALK diminished pSTAT3, pSTAT5, and CD30 expression but not pAkt or pPTEN in cultured cell lines.
  
  
  CONCLUSIONS
  We conclude that the PI3K/Akt pathway is activated in many, though not all, pediatric ALK+ ALCL. Our data suggest that activation of this pathway involves post-translational regulation of PTEN. Pharmacologic inhibition of activated ALK does not reduce modest levels of activated Akt as it does with the more abundant levels of activated STAT3 or STAT5. Future therapy of ALCL might, in selected patients, best combine agents inhibiting PI3K/Akt with those targeting ALK.
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Thakral
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hutchison
authors.forename: Antony
authors.initials: A
authors.lastname: Shrimpton
authors.forename: Donna
authors.initials: D
authors.lastname: Barrett
authors.forename: Joseph
authors.initials: J
authors.lastname: Laver
authors.forename: Michael
authors.initials: M
authors.lastname: Link
authors.forename: Devin R
authors.initials: DR
authors.lastname: Halleran
authors.forename: Sandra
authors.initials: S
authors.lastname: Hudson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human