Get access

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

Authors

  • Naoto Morishita MD,

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author
  • Hirokazu Tsukahara MD, PhD,

    Corresponding author
    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    • Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
    Search for more papers by this author
  • Kosuke Chayama MD, PhD,

    1. Department of Pediatrics, Toyonaka Municipal Hospital, Toyonaka, Japan
    Search for more papers by this author
  • Toshiaki Ishida MD, PhD,

    1. Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
    Search for more papers by this author
  • Kana Washio MD,

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author
  • Takako Miyamura MD, PhD,

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author
  • Nobuko Yamashita MD, PhD,

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author
  • Megumi Oda MD, PhD,

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author
  • Tsuneo Morishima MD, PhD

    1. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
    Search for more papers by this author

  • Conflict of interest: Nothing to declare.

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.

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. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

Ancillary