title: Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.
abstract: BACKGROUND
  Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL.
  
  
  METHODS
  We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs.
  
  
  RESULTS
  P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance.
  
  
  CONCLUSIONS
  These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL.
authors.affiliation: Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Morishita
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.forename: Kosuke
authors.initials: K
authors.lastname: Chayama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishida
authors.forename: Kana
authors.initials: K
authors.lastname: Washio
authors.forename: Takako
authors.initials: T
authors.lastname: Miyamura
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yamashita
authors.forename: Megumi
authors.initials: M
authors.lastname: Oda
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Morishima
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D011239:Prednisolone / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D011239:Prednisolone; D051057:Proto-Oncogene Proteins c-akt