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LEADING ARTICLE Phosphoinositide 3-Kinase/Akt Signaling Pathway and Its Therapeutical Implications for Human Acute Myeloid Leuke

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LEADING ARTICLE Phosphoinositide 3-Kinase/Akt Signaling Pathway and Its Therapeutical Implications for Human Acute Myeloid Leuke Leukemia (2006) 20, 911–928 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu LEADING ARTICLE Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia AM Martelli1,2, M Nya˚kern1, G Tabellini3, R Bortul4, PL Tazzari5, C Evangelisti1 and L Cocco1 1Cell Signalling Laboratory, Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Sezione di Anatomia Umana, Universita` di Bologna, Bologna, Italy; 2ITOI-CNR, c/o IOR, Bologna, Italy; 3Dipartimento di Scienze Biomediche e Biotecnologie, Sezione di Citologia e Istologia, Universita` di Brescia, Brescia, Italy; 4Dipartimento di Morfologia Umana Normale, Universita` di Trieste, Trieste, Italy and 5Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna, Italy The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is the 1970s,1–3 and patients with AML arising out of myelodys- crucial to many aspects of cell growth, survival and apoptosis, plastic syndrome (MDS) or who are older than 60 years do even and its constitutive activation has been implicated in the both 4 the pathogenesis and the progression of a wide variety of worse. Therefore, there remains a need for new, rationally neoplasias. Hence, this pathway is an attractive target for the designed, minimally toxic, effective therapies for AML. development of novel anticancer strategies. Recent studies Several independent laboratories have demonstrated that showed that PI3K/Akt signaling is frequently activated in acute AML arises from leukemic stem cells (LSCs) that have an myeloid leukemia (AML) patient blasts and strongly contributes extended phenotype lineage negative (linÀ), CD34 þ , CD38À, to proliferation, survival and drug resistance of these cells. CD123 þ , CD33 þ , CD13 þ /À.5,6 Indeed, injection of these cells Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small into immunocompromised nonobese diabetic/severe-combined molecules designed to selectively target key components of immunodeficient (NOD/SCID) mice leads to a disease with this signal transduction cascade induce apoptosis and/or phenotypic and molecular characteristics of human AML. Over markedly increase conventional drug sensitivity of AML blasts the last few years, remarkable progress has been made in the in vitro. Thus, inhibitory molecules are currently being devel- elucidation of the molecular pathogenesis of AML. A recent ‘two oped for clinical use either as single agents or in combination hits’ model has suggested that AML development requires with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in multiple genetic changes that deregulate different cell pro- 7 particular, for insulin signaling, so that its blockade in vivo grams. Transcription factor fusion proteins such as AML1/ETO, might cause severe systemic side effects. In this review, we PML-RARa, CBFb/MYH11 or MLL/AF9 block myeloid cell summarize the existing knowledge about PI3K/Akt signaling in differentiation by repressing target genes, thus providing one AML cells and we examine the rationale for targeting this necessary event for leukemogenesis.8,9 Disordered cell growth fundamental signal transduction network by means of selective pharmacological inhibitors. and upregulation of cell survival genes is a proposed necessary Leukemia (2006) 20, 911–928. doi:10.1038/sj.leu.2404245; second event. Mutations in growth regulatory genes such as 10–12 published online 27 April 2006 FLT3, Ras and c-Kit are common in AML patients. The most Keywords: signal transduction networks; 3-phosphorylated inositol recent data provide evidence of great interdependence between lipids; apoptosis; drug resistance; targeted molecular therapy these two classes of molecular events. Indeed, changes in the transcriptional control in hematopoietic cells modify the arrays of signal transduction effectors available for growth factor Introduction receptors, whereas activating mutations in signal transduction molecules induce alterations in the activity and expression of Acute myeloid leukemia (AML) is a heterogeneous group of several transcription factors that are essential for normal myeloid malignant hematopoietic disorders characterized by uncon- differentiation.13,14 trolled proliferation of clonal neoplastic cells and accumulation The phosphoinositide 3-kinase (PI3K)/Akt signaling network is in the bone marrow of blasts with an impaired differentiation crucial to widely divergent physiological processes that include program which are blocked at various maturation steps and cell cycle progression, differentiation, transcription, translation resistant to cell death. Acute myeloid leukemia accounts for and apoptosis.15,16 It is targeted by genomic aberrations approximately 80% of all adult leukemias and its overall including amplification, mutation and rearrangement more incidence has been stable or slowly increasing over the last frequently than any other pathway in human cancer, with the 15–20 years.1 Despite considerable advances in the diagnosis of possible exception of the p53 and retinoblastoma pathways. the different AML subtypes and progress in therapeutic Activation of PI3K/Akt signaling results in disturbance of control approaches, current chemotherapies produce only initial remis- of cell proliferation and apoptosis, ensuing in competitive sion, so that most patients will relapse and die from the disease. growth advantage for tumor cells.17–19 Furthermore, it is now The 5-year survival rate of AML has hovered at 15–30% since clear that PI3K/Akt axis upregulation may be one of the major factors undermining successful antineoplastic treatment, thus Correspondence: Dr AM Martelli, Dipartimento di Scienze Anato- portending a poor prognosis in many cancer types.20 Therefore, miche Umane e Fisiopatologia dell’Apparato Locomotore, Sezione di the PI3K/Akt pathway is an attractive target for the development Anatomia Umana, Cell Signalling Laboratory, Universita` di Bologna, of novel therapeutic strategies in patients with various tumor Bologna 40126, Italy. E-mail: [email protected] types. Received 23 February 2006; accepted 27 March 2006; published Several recent papers have highlighted that the PI3K/Akt axis online 27 April 2006 is activated in AML.21–24 Remarkably, both the disease-free PI3K/Akt signaling in AML AM Martelli et al 912 survival and overall survival were significantly shorter in AML organs and a selective impairment of brain development, cases with upregulated PI3K/Akt pathway.25 Therefore, this respectively.34,35 signal transduction cascade may represent a valid target for Akt contains an NH2-terminal pleckstrin homology (PH) innovative therapeutic treatments of AML patients. The main domain, which interacts with the phosphorylated lipid products aim of this review is to discuss potential antineoplastic strategies of PI3K (mainly PtdIns (3,4,5)P3 and, to a lesser extent, targeting this signaling network in AML. However, we shall phosphatidylinositol 3,4 bisphosphate (PtdIns (3,4,)P2)) synthe- begin with a general outline of the mechanisms that govern sized at the plasma membrane. Akt recruitment at the plasma PI3K/Akt activation and of the responses generated along this membrane results in a conformational change, which enables signaling cascade with a particular emphasis placed on AML. the activation loop of the kinase to be phosphorylated on Thr 308 by phosphoinositide-dependent protein kinase-1 (PDK-1, which also requires 3-phosphorylated inositol lipids for activa- PI3K family of isozymes and their activation tion and plasma membrane translocation) and at Ser 473 in the C-terminal hydrophobic motif by a kinase (often referred The large family of PI3K lipid kinases in mammalian cells has to as PDK-2) whose identity, despite intense investigation, been categorized into three classes, referred to as I, II and III, remains highly controversial.15,16 Candidate PDK-2s include each of which has its own characteristics in terms of molecular integrin-linked kinase, DNA-dependent protein kinase and structure and substrate specificity.26 Class I PI3Ks are the best mitogen-activated protein kinase-kinase 2. The corresponding understood and are key players of multiple intracellular phosphorylation sites of Akt2 are Thr 309 and Ser 474, whereas signaling networks that integrate a wide variety of signals, those of Akt3 are Thr 305 and Ser 472.15 Recent evidence has engaged by many polypeptide growth factors. For this reason, highlighted that Ser 473 phosphorylation precedes Thr 308 they will be the only isoforms considered relevant to this review. phosphorylation and actually enhances it (see Sarbassov et al.36 Growth factor receptors drive activation of class I PI3Ks either and references therein). directly or via associated tyrosine kinases, heterotrimeric G Furthermore, it has been shown that additional phosphory- proteins or Ras. Class I PI3K preferred in vivo substrate is lative steps may increase Akt activation, including phosphory- 15 phosphatidylinositol 4,5 bisphosphate (PtdIns (4,5)P2), which is lation of multiple tyrosine residues, and phosphorylation on phosphorylated to yield phosphatidylinositol 3,4,5 trisphosphate Ser 129 through casein kinase 2 (CK2),37 but relevance of these (PtdIns (3,4,5)P3). They are further divided into class IA and IB phosphorylative events awaits full elucidation. Phosphorylated
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