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Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation

¹ Centre for Cell Signalling, Queen Mary University of London, Institute of Cancer, Barts and The London School of Medicine, John Vane Science Centre and ² UCL Cancer Institute, University College London, London, United Kingdom

Requests for reprints: Asim Khwaja, UCL Cancer Institute, Paul O'Gorman Building, University College London, London, WC1E 6BT, UK. Phone: 44-20-7679-6554; E-mail: a.khwaja{at}ucl.ac.uk or Bart Vanhaesebroeck, Centre for Cell Signalling, Institute of Cancer, Barts and The London School of Medicine, John Vane Science Centre, London EC1M 6BQ, UK. Phone: 44-20-7882-8201; E-mail: bart.vanh{at}qmul.ac.uk.

Key Words: APL • PI3K • cell differentiation • p110β • ATRA

We have investigated the role of phosphoinositide 3-kinases (PI3Ks) in the in vitro pathophysiology of acute promyelocytic leukemia (APL) and in the response to treatment with all-trans-retinoic-acid (ATRA), utilizing a range of novel inhibitors that target individual or all catalytic class I isoforms of PI3K (p110, p110β, p110, and p110). ATRA-induced phosphorylation of the Akt kinase and ribosomal S6 protein in APL cells was sensitive to class I PI3K, and p110β or p110 inhibitors, and to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In primary APL, inhibition of p110β or p110 triggered apoptosis in the absence or presence of ATRA. Class I PI3K inhibition could also reverse ATRA-induced protection of these cells against doxorubicin and arsenic trioxide, correlating with impaired induction of the antiapoptotic MCL-1 protein. The differentiation-inducing effects of ATRA were not dependent on class I PI3K/mTOR. In summary, class I PI3K signaling, mediated by p110β and p110, plays an important role in basal and ATRA-induced cell survival mechanisms in APL. Addition of PI3K inhibitors to induction treatment regimens may provide therapeutic benefit. [Cancer Res 2009;69(3):1027–36]