Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia

Pediatr Blood Cancer. 2012 Jul 15;59(1):83-9. doi: 10.1002/pbc.24034. Epub 2011 Dec 19.


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.

Procedure: 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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Apoptosis / drug effects
  • Blast Crisis* / drug therapy
  • Blast Crisis* / enzymology
  • Blast Crisis* / mortality
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Dexamethasone / administration & dosage
  • Disease-Free Survival
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm*
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Infant
  • Male
  • Phosphorylation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / enzymology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / mortality
  • Prednisolone / administration & dosage
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Survival Rate
  • Vincristine / administration & dosage


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Vincristine
  • Dexamethasone
  • Doxorubicin
  • Prednisolone
  • Proto-Oncogene Proteins c-akt