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Class I Phosphoinositide 3-Kinases in Normal and Pathologic Hematopoietic Cells

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Phosphoinositides and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 362))

Abstract

Class I phosphoinositide 3-kinases which produce the D3-phosphoinositide second messenger phosphatidylinositol 3,4,5-trisphosphate in response to membrane receptors activation play a critical role in cell proliferation, survival, metabolism, and motility. These lipid kinases and the phosphatases regulating the level of D3-phosphoinositides have been an intense area of research these last two decades. The class I phosphoinositide 3-kinases signaling is found aberrantly activated in numerous human cancers, including in malignant hemopathies, and are important therapeutic targets for cancer therapy. Haematopoiesis is an ongoing process which generates the distinct blood cell types from a common hematopoietic stem cell through the action of a variety of cytokines. In the human adult hematopoiesis occurs primarily in the bone marrow, and defects in hematopoiesis result in diseases, such as anemia, thrombocytopenia, myeloproliferative syndromes, or leukemia. Here we give a brief overview of the role of class I phosphoinositide 3-kinases in hematopoietic stem cells, in hematopoietic lineage development and in leukemia, particularly in acute myeloid leukemia and summarize the potential therapeutic implications.

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References

  • Aggerholm A, Gronbaek K, Guldberg P, Hokland P (2000) Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol 65:109–113

    PubMed  CAS  Google Scholar 

  • Angeloni D, Danilkovitch-Miagkova A, Ivanova T, Braga E, Zabarovsky E, Lerman MI (2007) Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 26:4499–4512

    PubMed  CAS  Google Scholar 

  • Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–161

    PubMed  CAS  Google Scholar 

  • Bai H, Xu R, Cao Z, Wei D, Wang C (2011) Involvement of miR-21 in resistance to daunorubicin by regulating PTEN expression in the leukaemia K562 cell line. FEBS Lett 585:402–408

    PubMed  CAS  Google Scholar 

  • Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, Vanhaesebroeck B (2006) Key role of the p110delta isoform of PI3 K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107:642–650

    PubMed  CAS  Google Scholar 

  • Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B, Khwaja A (2006) A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 25:6648–6659

    PubMed  CAS  Google Scholar 

  • Billottet C, Banerjee L, Vanhaesebroeck B, Khwaja A (2009) Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation. Cancer Res 69:1027–1036

    PubMed  CAS  Google Scholar 

  • Bone HK, Welham MJ (2007) Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis. J Cell Sci 120:1752–1762

    PubMed  CAS  Google Scholar 

  • Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

    PubMed  CAS  Google Scholar 

  • Bouscary D, Pene F, Claessens YE, Muller O, Chretien S, Fontenay-Roupie M, Gisselbrecht S, Mayeux P, Lacombe C (2003) Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood 101:3436–3443

    PubMed  CAS  Google Scholar 

  • Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M et al (2005) Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 65:9643–9650

    PubMed  CAS  Google Scholar 

  • Buitenhuis M, Verhagen LP, van Deutekom HW, Castor A, Verploegen S, Koenderman L, Jacobsen SE, Coffer PJ (2008) Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood 111:112–121

    PubMed  CAS  Google Scholar 

  • Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N, Kipps TJ, Burger JA (2005) Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 106:1824–1830

    PubMed  CAS  Google Scholar 

  • Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M et al (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6:251–264

    PubMed  CAS  Google Scholar 

  • Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846

    PubMed  CAS  Google Scholar 

  • Carlton JG, Cullen PJ (2005) Coincidence detection in phosphoinositide signaling. Trends Cell Biol 15:540–547

    PubMed  CAS  Google Scholar 

  • Chabanon A, Desterke C, Rodenburger E, Clay D, Guerton B, Boutin L, Bennaceur-Griscelli A, Pierre-Louis O, Uzan G, Abecassis L et al (2008) A cross-talk between stromal cell-derived factor-1 and transforming growth factor-beta controls the quiescence/cycling switch of CD34(+) progenitors through FoxO3 and mammalian target of rapamycin. Stem Cells 26:3150–3161

    PubMed  CAS  Google Scholar 

  • Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, Park S, Green AS, Ifrah N, Dreyfus F et al (2010a) Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3 K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica 95:415–423

    PubMed  CAS  Google Scholar 

  • Chapuis N, Tamburini J, Green AS, Vignon C, Bardet V, Neyret A, Pannetier M, Willems L, Park S, Macone A et al (2010b) Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res 16:5424–5435

    PubMed  CAS  Google Scholar 

  • Chetram MA, Don-Salu-Hewage AS, Hinton CV (2011) ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. Biochem Biophys Res Commun 410:195–200

    PubMed  CAS  Google Scholar 

  • Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H, et al (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 1:ra3

    Google Scholar 

  • Cornejo MG, Mabialah V, Sykes SM, Khandan T, Lo Celso C, Lopez CK, Rivera-Munoz P, Rameau P, Tothova Z, Aster JC et al (2011) Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification. Blood 118:1264–1273

    PubMed  CAS  Google Scholar 

  • Costa C, Hirsch E (2010) More than just kinases: the scaffolding function of PI3 K. Curr Top Microbiol Immunol 346:171–181

    PubMed  CAS  Google Scholar 

  • Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657

    PubMed  Google Scholar 

  • Dick JE (2009) Looking ahead in cancer stem cell research. Nat Biotechnol 27:44–46

    PubMed  CAS  Google Scholar 

  • Doepfner KT, Spertini O, Arcaro A (2007) Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia 21:1921–1930

    PubMed  CAS  Google Scholar 

  • Dos Santos C, Demur C, Bardet V, Prade-Houdellier N, Payrastre B, Recher C (2008) A critical role for Lyn in acute myeloid leukemia. Blood 111:2269–2279

    PubMed  Google Scholar 

  • Fialin C, Larrue C, Vergez F, Sarry JE, Bertoli S, Mansat- De Mas V, Demur C, Delabesse E, Payrastre B, Manenti S, Roche S, Recher C (2012) The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia (in press)

    Google Scholar 

  • Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B (2010) Activity of any class IA PI3 K isoform can sustain cell proliferation and survival. Proc Natl Acad Sci U S A 107:11381–11386

    PubMed  CAS  Google Scholar 

  • Gallay N, Dos Santos C, Cuzin L, Bousquet M, Simmonet Gouy V, Chaussade C, Attal M, Payrastre B, Demur C, Recher C (2009) The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia. Leukemia 23:1029–1038

    PubMed  CAS  Google Scholar 

  • Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B (2007) Class IA phosphoinositide 3-kinases are obligate p85–p110 heterodimers. Proc Natl Acad Sci U S A 104:7809–7814

    PubMed  CAS  Google Scholar 

  • Gibbs KD Jr, Jager A, Crespo O, Goltsev Y, Trejo A, Richard CE, Nolan GP (2012) Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-Driven AML. Cell Stem Cell 10:210–217

    PubMed  CAS  Google Scholar 

  • Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, Woll P, Mead A, Alford KA, Rout R et al (2011) Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19:138–152

    PubMed  CAS  Google Scholar 

  • Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M (2008) Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell 3:207–220

    PubMed  CAS  Google Scholar 

  • Gratacap MP, Guillermet-Guibert J, Martin V, Chicanne G, Tronchere H, Gaits-Iacovoni F, Payrastre B (2011) Regulation and roles of PI3 Kbeta, a major actor in platelet signaling and functions. Adv Enzyme Regul 51:106–116

    PubMed  CAS  Google Scholar 

  • Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, Dahlberg S, Neuberg D, Moreau LA, Winter SS et al (2009) High frequency of PTEN, PI3 K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114:647–650

    PubMed  CAS  Google Scholar 

  • Hashimoto K, Matsumura I, Tsujimura T, Kim DK, Ogihara H, Ikeda H, Ueda S, Mizuki M, Sugahara H, Shibayama H et al (2003) Necessity of tyrosine 719 and phosphatidylinositol 3’-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation. Blood 101:1094–1102

    PubMed  CAS  Google Scholar 

  • Hazen AL, Smith MJ, Desponts C, Winter O, Moser K, Kerr WG (2009) SHIP is required for a functional hematopoietic stem cell niche. Blood 113:2924–2933

    PubMed  CAS  Google Scholar 

  • Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM, Borowski A, Jirik F, Krystal G, Humphries RK (1998) Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev 12:1610–1620

    PubMed  CAS  Google Scholar 

  • Helgason CD, Antonchuk J, Bodner C, Humphries RK (2003) Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice. Blood 102:3541–3547

    PubMed  CAS  Google Scholar 

  • Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, Chi JT, Salter AB, Lento WE, Reya T et al (2010) Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 16:475–482

    PubMed  CAS  Google Scholar 

  • Hu L, Shi Y, Hsu JH, Gera J, Van Ness B, Lichtenstein A (2003) Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 101:3126–3135

    PubMed  CAS  Google Scholar 

  • Huddleston H, Tan B, Yang FC, White H, Wenning MJ, Orazi A, Yoder MC, Kapur R, Ingram DA (2003) Functional p85alpha gene is required for normal murine fetal erythropoiesis. Blood 102:142–145

    PubMed  CAS  Google Scholar 

  • Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y et al (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 11:507–514

    PubMed  CAS  Google Scholar 

  • Jang YY, Sharkis SJ (2007) A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110:3056–3063

    PubMed  CAS  Google Scholar 

  • Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Ruckle T, Camps M et al (2007) Inactivation of PI3 Kgamma and PI3 Kdelta distorts T-cell development and causes multiple organ inflammation. Blood 110:2940–2947

    PubMed  CAS  Google Scholar 

  • Jotta PY, Ganazza MA, Silva A, Viana MB, da Silva MJ, Zambaldi LJ, Barata JT, Brandalise SR, Yunes JA (2010) Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 24:239–242

    PubMed  CAS  Google Scholar 

  • Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA (2010) AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 115:4030–4038

    PubMed  CAS  Google Scholar 

  • Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459

    PubMed  CAS  Google Scholar 

  • Kharas MG, Okabe R, Ganis JJ, Gozo M, Khandan T, Paktinat M, Gilliland DG, Gritsman K (2010) Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 115:1406–1415

    PubMed  CAS  Google Scholar 

  • Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8:290–301

    PubMed  CAS  Google Scholar 

  • Kobayashi H, Butler JM, O’Donnell R, Kobayashi M, Ding BS, Bonner B, Chiu VK, Nolan DJ, Shido K, Benjamin L et al (2010) Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12:1046–1056

    PubMed  CAS  Google Scholar 

  • Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, Estey EH, Andreeff M (2006) Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 108:2358–2365

    PubMed  CAS  Google Scholar 

  • Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG et al (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442:818–822

    PubMed  CAS  Google Scholar 

  • Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G (1998) Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 17:3714–3725

    PubMed  CAS  Google Scholar 

  • Kulkarni S, Sitaru C, Jakus Z, Anderson KE, Damoulakis G, Davidson K, Hirose M, Juss J, Oxley D, Chessa TA, et al (2011) PI3 Kbeta plays a critical role in neutrophil activation by immune complexes. Sci Signal 4:ra23

    Google Scholar 

  • Lee EJ, Kim N, Kang KH, Kim JW (2011) Phosphorylation/inactivation of PTEN by Akt-independent PI3 K signaling in retinal pigment epithelium. Biochem Biophys Res Commun 414:384–389

    PubMed  CAS  Google Scholar 

  • Lemmon MA (2008) Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol 9:99–111

    PubMed  CAS  Google Scholar 

  • Liesveld JL, Bechelli J, Rosell K, Lu C, Bridger G, Phillips G 2nd, Abboud CN (2007) Effects of AMD3100 on transmigration and survival of acute myelogenous leukemia cells. Leuk Res 31:1553–1563

    PubMed  CAS  Google Scholar 

  • Liu TC, Lin PM, Chang JG, Lee JP, Chen TP, Lin SF (2000) Mutation analysis of PTEN/MMAC1 in acute myeloid leukemia. Am J Hematol 63:170–175

    PubMed  CAS  Google Scholar 

  • Lo TC, Barnhill LM, Kim Y, Nakae EA, Yu AL, Diccianni MB (2009) Inactivation of SHIP1 in T-cell acute lymphoblastic leukemia due to mutation and extensive alternative splicing. Leuk Res 33:1562–1566

    PubMed  CAS  Google Scholar 

  • Luo JM, Yoshida H, Komura S, Ohishi N, Pan L, Shigeno K, Hanamura I, Miura K, Iida S, Ueda R et al (2003) Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 17:1–8

    PubMed  CAS  Google Scholar 

  • Machado-Neto JA, Traina F, Lazarini M, Campos Pde M, Pagnano KB, Lorand-Metze I, Costa FF, Saad ST (2011) Screening for hotspot mutations in PI3 K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes. Clinics (Sao Paulo) 66:793–799

    Google Scholar 

  • Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Manzoli L, McCubrey JA (2009) Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opin Investig Drugs 18:1333–1349

    PubMed  CAS  Google Scholar 

  • Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, Vanhaesebroeck B, Payrastre B, Gratacap MP (2010) Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood 115:2008–2013

    PubMed  CAS  Google Scholar 

  • McCrea HJ, De Camilli P (2009) Mutations in phosphoinositide metabolizing enzymes and human disease. Physiology (Bethesda) 24:8–16

    CAS  Google Scholar 

  • McLornan DP, McMullin MF, Johnston P, Longley DB (2007) Molecular mechanisms of drug resistance in acute myeloid leukaemia. Expert Opin Drug Metab Toxicol 3:363–377

    PubMed  CAS  Google Scholar 

  • Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, Lee ST, Lee MH, Hahn JS, Ko YW (2003) Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 17:995–997

    PubMed  CAS  Google Scholar 

  • Mise J, Dembitz V, Banfic H, Visnjic D (2011) Combined inhibition of PI3K and mTOR exerts synergistic antiproliferative effect, but diminishes differentiative properties of rapamycin in acute myeloid leukemia cells. Pathol Oncol Res 17:645–656

    PubMed  CAS  Google Scholar 

  • Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1:101–112

    PubMed  CAS  Google Scholar 

  • Moody JL, Xu L, Helgason CD, Jirik FR (2004) Anemia, thrombocytopenia, leukocytosis, extramedullary hematopoiesis, and impaired progenitor function in Pten ± SHIP-/- mice: a novel model of myelodysplasia. Blood 103:4503–4510

    PubMed  CAS  Google Scholar 

  • Nakao T, Geddis AE, Fox NE, Kaushansky K (2008) PI3 K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1). Cell Cycle 7:257–266

    PubMed  CAS  Google Scholar 

  • Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA (2009) Isoform-selective phosphoinositide 3’-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood 113:5549–5557

    PubMed  CAS  Google Scholar 

  • Nyakern M, Tazzari PL, Finelli C, Bosi C, Follo MY, Grafone T, Piccaluga PP, Martinelli G, Cocco L, Martelli AM (2006) Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients. Leukemia 20:230–238

    PubMed  CAS  Google Scholar 

  • Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, Shokat K, Ridley AJ, Vanhaesebroeck B (2008) Distinct roles of class IA PI3 K isoforms in primary and immortalised macrophages. J Cell Sci 121:4124–4133

    PubMed  CAS  Google Scholar 

  • Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L, Knight ZA, Shokat KM, Azar N, Viguie F et al (2008) PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22:1698–1706

    PubMed  CAS  Google Scholar 

  • Payrastre B, Missy K, Giuriato S, Bodin S, Plantavid M, Gratacap M (2001) Phosphoinositides: key players in cell signalling, in time and space. Cell Signal 13:377–387

    PubMed  CAS  Google Scholar 

  • Payrastre B, Gaits-Iacovoni F, Sansonetti P, Tronchere H (2012) Phosphoinositides and cellular pathogens. Subcell Biochem 59:363–388

    PubMed  Google Scholar 

  • Pendaries C, Tronchere H, Plantavid M, Payrastre B (2003) Phosphoinositide signaling disorders in human diseases. FEBS Lett 546:25–31

    PubMed  CAS  Google Scholar 

  • Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM, Benzaquen D, Laurent G, Huguet F, Payrastre B (2005) Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105:2527–2534

    PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    PubMed  CAS  Google Scholar 

  • Rommel C, Camps M, Ji H (2007) PI3 K delta and PI3 K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 7:191–201

    PubMed  CAS  Google Scholar 

  • Ruvolo PP, Qui YH, Coombes KR, Zhang N, Ruvolo VR, Borthakur G, Konopleva M, Andreeff M, Kornblau SM (2011) Low expression of PP2A regulatory subunit B55alpha is associated with T308 phosphorylation of AKT and shorter complete remission duration in acute myeloid leukemia patients. Leukemia 25:1711–1717

    PubMed  CAS  Google Scholar 

  • Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C, Swider CR, Strzelecki AC, Cavelier C, Recher C et al (2011) Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice. J Clin Invest 121:384–395

    PubMed  CAS  Google Scholar 

  • Sasaki J, Kofuji S, Itoh R, Momiyama T, Takayama K, Murakami H, Chida S, Tsuya Y, Takasuga S, Eguchi S (2010) The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death. Nature 465:497–501

    PubMed  CAS  Google Scholar 

  • Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441:1075–1079

    PubMed  CAS  Google Scholar 

  • Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, Nowill AE, Leslie NR, Cardoso AA, Barata JT (2008) PTEN posttranslational inactivation and hyperactivation of the PI3 K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 118:3762–3774

    PubMed  CAS  Google Scholar 

  • Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N et al (2005) Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106:1063–1066

    PubMed  CAS  Google Scholar 

  • Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM et al (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146:697–708

    PubMed  CAS  Google Scholar 

  • Tabellini G, Cappellini A, Tazzari PL, Fala F, Billi AM, Manzoli L, Cocco L, Martelli AM (2005) Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells. J Cell Physiol 202:623–634

    PubMed  CAS  Google Scholar 

  • Tamburini J, Elie C, Bardet V, Chapuis N, Park S, Broet P, Cornillet-Lefebvre P, Lioure B, Ugo V, Blanchet O et al (2007) Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. Blood 110:1025–1028

    PubMed  CAS  Google Scholar 

  • Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, Ifrah N, Dreyfus F, Mayeux P, Lacombe C et al (2008) Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood 111:379–382

    PubMed  CAS  Google Scholar 

  • Tamura N, Hazeki K, Okazaki N, Kametani Y, Murakami H, Takaba Y, Ishikawa Y, Nigorikawa K, Hazeki O (2009) Specific role of phosphoinositide 3-kinase p110alpha in the regulation of phagocytosis and pinocytosis in macrophages. Biochem J 423:99–108

    PubMed  CAS  Google Scholar 

  • Tazzari PL, Tabellini G, Bortul R, Papa V, Evangelisti C, Grafone T, Martinelli G, McCubrey JA, Martelli AM (2007a) The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion. Leukemia 21:886–896

    PubMed  CAS  Google Scholar 

  • Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, Martinelli G, Conte R, Cocco L, McCubrey JA et al (2007b) Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 21:427–438

    PubMed  CAS  Google Scholar 

  • Tibes R, Kornblau SM, Qiu Y, Mousses SM, Robbins C, Moses T, Carpten JD (2008) PI3 K/AKT pathway activation in acute myeloid leukaemias is not associated with AKT1 pleckstrin homology domain mutation. Br J Haematol 140:344–347

    PubMed  CAS  Google Scholar 

  • Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325–339

    PubMed  CAS  Google Scholar 

  • Tuveson DA, Carter RH, Soltoff SP, Fearon DT (1993) CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 260:986–989

    PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Jones GE, Allen WE, Zicha D, Hooshmand-Rad R, Sawyer C, Wells C, Waterfield MD, Ridley AJ (1999) Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol 1:69–71

    PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC (2005) Signalling by PI3 K isoforms: insights from gene-targeted mice. Trends Biochem Sci 30:194–204

    PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3 K signalling. Nat Rev Mol Cell Biol 11:329–341

    PubMed  CAS  Google Scholar 

  • Walter RB, Raden BW, Hong TC, Flowers DA, Bernstein ID, Linenberger ML (2003) Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood 102:1466–1473

    PubMed  CAS  Google Scholar 

  • Watts KL, Delaney C, Humphries RK, Bernstein ID, Kiem HP (2010) Combination of HOXB4 and Delta-1 ligand improves expansion of cord blood cells. Blood 116:5859–5866

    PubMed  CAS  Google Scholar 

  • Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M (2003) Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102:972–980

    PubMed  CAS  Google Scholar 

  • Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–482

    PubMed  CAS  Google Scholar 

  • Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T, Shimabe M, Nakagawa M et al (2011) Evi1 represses PTEN expression and activates PI3 K/AKT/mTOR via interactions with polycomb proteins. Blood 117:3617–3628

    PubMed  CAS  Google Scholar 

  • Zanella F, Rosado A, Garcia B, Carnero A, Link W (2008) Chemical genetic analysis of FOXO nuclear-cytoplasmic shuttling by using image-based cell screening. Chem Bio Chem 9:2229–2237

    PubMed  CAS  Google Scholar 

  • Zebedin E, Simma O, Schuster C, Putz EM, Fajmann S, Warsch W, Eckelhart E, Stoiber D, Weisz E, Schmid JA et al (2008) Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance. Blood 112:4655–4664

    PubMed  CAS  Google Scholar 

  • Zeng Z, Samudio IJ, Munsell M, An J, Huang Z, Estey E, Andreeff M, Konopleva M (2006) Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. Mol Cancer Ther 5:3113–3121

    PubMed  CAS  Google Scholar 

  • Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ et al (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425:836–841

    PubMed  CAS  Google Scholar 

  • Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, Haug JS, Rupp D, Porter-Westpfahl KS, Wiedemann LM et al (2006) PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441:518–522

    PubMed  CAS  Google Scholar 

  • Zhou M, Gu L, Findley HW, Jiang R, Woods WG (2003) PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res 63:6357–6362

    PubMed  CAS  Google Scholar 

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Vergez, F., Recher, C., Payrastre, B. (2012). Class I Phosphoinositide 3-Kinases in Normal and Pathologic Hematopoietic Cells. In: FALASCA, M. (eds) Phosphoinositides and Disease. Current Topics in Microbiology and Immunology, vol 362. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5025-8_8

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