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.
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.
Authors: Ivana Gojo; Alexander Perl; Selina Luger; Maria R Baer; Kelly J Norsworthy; Kenneth S Bauer; Michael Tidwell; Stephanie Fleckinger; Martin Carroll; Edward A Sausville Journal: Invest New Drugs Date: 2013-02-27 Impact factor: 3.850
Authors: Erich Piovan; Jiyang Yu; Valeria Tosello; Daniel Herranz; Alberto Ambesi-Impiombato; Ana Carolina Da Silva; Marta Sanchez-Martin; Arianne Perez-Garcia; Isaura Rigo; Mireia Castillo; Stefano Indraccolo; Justin R Cross; Elisa de Stanchina; Elisabeth Paietta; Janis Racevskis; Jacob M Rowe; Martin S Tallman; Giuseppe Basso; Jules P Meijerink; Carlos Cordon-Cardo; Andrea Califano; Adolfo A Ferrando Journal: Cancer Cell Date: 2013-11-27 Impact factor: 31.743
Authors: Rachel M A Linger; Alisa B Lee-Sherick; Deborah DeRyckere; Rebecca A Cohen; Kristen M Jacobsen; Amy McGranahan; Luis N Brandão; Amanda Winges; Kelly K Sawczyn; Xiayuan Liang; Amy K Keating; Aik Choon Tan; H Shelton Earp; Douglas K Graham Journal: Blood Date: 2013-07-16 Impact factor: 22.113
Authors: L M Neri; A Cani; A M Martelli; C Simioni; C Junghanss; G Tabellini; F Ricci; P L Tazzari; P Pagliaro; J A McCubrey; S Capitani Journal: Leukemia Date: 2013-07-29 Impact factor: 11.528