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

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.