Nuclear PI-PLC β1 and Myelodysplastic Syndromes: From Bench to Clinics

  • Sara Mongiorgi
  • Matilde Y. Follo
  • Cristina Clissa
  • Roberto Giardino
  • Milena Fini
  • Lucia Manzoli
  • Giulia Ramazzotti
  • Roberta Fiume
  • Carlo Finelli
  • Lucio Cocco
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 362)


Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. A number of MDS progresses to acute myeloid leukemia (AML) with the involvement of genetic and epigenetic mechanisms affecting PI-PLC β1. The molecular mechanisms underlying the MDS evolution to AML are still unclear, even though it is now clear that the nuclear signaling elicited by PI-PLC β1, Cyclin D3, and Akt plays an important role in the control of the balance between cell cycle progression and apoptosis in both normal and pathologic conditions. Moreover, a correlation between other PI-PLCs, such as PI-PLC β3, kinases and phosphatases has been postulated in MDS pathogenesis. Here, we review the findings hinting at the role of nuclear lipid signaling pathways in MDS, which could become promising therapeutic targets.


Acute Myeloid Leukemia JAK2 V617F47 International Prognostic Scoring System DNMT Inhibitor Epigenetic Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Italian MIUR-FIRB (Human Proteome Net and Accordi di Programma 2010), Italian MIUR PRIN and Celgene Corp.


  1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199PubMedGoogle Scholar
  2. Braiteh F, Soriano AO, Garcia-Manero G et al (2008) Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res 14:6296–6301PubMedCrossRefGoogle Scholar
  3. Cain JA, Xiang Z, O’Neal J et al (2007) Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage. Blood 109:3906–3914PubMedCrossRefGoogle Scholar
  4. Choudhary C, Brandts C, Schwable J et al (2007) Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood 110:370–374PubMedCrossRefGoogle Scholar
  5. Cooper AB, Sawai CM, Sicinska E, Powers SE, Sicinski P, Clark MR, Aifantis I (2006) A unique function for cyclin D3 in early B cell development. Nat Immunol 7:489–497PubMedCrossRefGoogle Scholar
  6. Daskalakis M, Nguyen TT, Nguyen C et al (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100:2957–2964PubMedCrossRefGoogle Scholar
  7. Faenza I, Bregoli L, Ramazzotti G et al (2008) Nuclear phospholipase Cbeta1 and cellular differentiation. Front Biosci 13:2452–2463PubMedCrossRefGoogle Scholar
  8. Faenza I, Matteucci A, Manzoli L et al (2000) A role for nuclear phospholipase Cbeta1 in cell cycle control. J Biol Chem 275:30520–30524PubMedCrossRefGoogle Scholar
  9. Faenza I, Ramazzotti G, Bavelloni A et al (2007) Inositide-dependent phospholipase C signaling mimics insulin in skeletal muscle differentiation by affecting specific regions of the cyclin D3 promoter. Endocrinology 148:1108–1117PubMedCrossRefGoogle Scholar
  10. Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10:223–232PubMedCrossRefGoogle Scholar
  11. Fenaux P, Raza A, Mufti GJ et al (2007) A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate—to high-risk myelodysplastic syndrome. Blood 109:4158–4163PubMedCrossRefGoogle Scholar
  12. Fiume R, Ramazzotti G, Teti G et al (2009) Involvement of nuclear PLCbeta1 in lamin B1 phosphorylation and G2/M cell cycle progression. FASEB J 23:957–966PubMedCrossRefGoogle Scholar
  13. Follo MY, Bosi C, Finelli C et al (2006) Real-time PCR as a tool for quantitative analysis of PI-PLCbeta1 gene expression in myelodysplastic syndrome. Int J Mol Med 18:267–271PubMedGoogle Scholar
  14. Follo MY, Finelli C, Bosi C et al (2008) PI-PLCbeta-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes. Leukemia 22:198–200PubMedCrossRefGoogle Scholar
  15. Follo MY, Finelli C, Clissa C et al (2009a) Phosphoinositide-phospholipase Cbeta1 mono-allelic deletion is associated with myelodysplastic syndromes evolution into acute myeloid leukemia. J Clin Oncol 27:782–790PubMedCrossRefGoogle Scholar
  16. Follo MY, Finelli C, Mongiorgi S et al (2009b) Reduction of phosphoinositide-phospholipase Cbeta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. Proc Natl Acad Sci U S A 106:16811–16816PubMedCrossRefGoogle Scholar
  17. Follo MY, Finelli C, Mongiorgi S et al (2011) Synergistic induction of PI-PLCbeta1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes. Leukemia 25:271–280PubMedCrossRefGoogle Scholar
  18. Follo MY, Mongiorgi S, Bosi C et al (2007) The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation. Cancer Res 67:4287–4294PubMedCrossRefGoogle Scholar
  19. Follo MY, Mongiorgi S, Finelli C et al (2010) Nuclear inositide signaling in myelodysplastic syndromes. J Cell Biochem 109:1065–1071PubMedGoogle Scholar
  20. Furukawa Y (2002) Cell cycle control genes and hematopoietic cell differentiation. Leuk Lymphoma 43:225–231PubMedCrossRefGoogle Scholar
  21. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMedGoogle Scholar
  22. Griffiths EA, Gore SD (2008) DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol 45:23–30PubMedCrossRefGoogle Scholar
  23. Jabbour E, Kantarjian HM, Koller C, Taher A (2008) Red blood cell transfusions and iron overload in the treatment of patients with myelodysplastic syndromes. Cancer 112:1089–1095PubMedCrossRefGoogle Scholar
  24. Kaminskas E, Farrell A, Abraham S et al (2005) Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11:3604–3608PubMedCrossRefGoogle Scholar
  25. Malcovati L, Germing U, Kuendgen A et al (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25:3503–3510PubMedCrossRefGoogle Scholar
  26. Martelli AM, Fiume R, Faenza I et al (2005) Nuclear phosphoinositide specific phospholipase C (PI-PLC)-beta1: a central intermediary in nuclear lipid-dependent signal transduction. Histol Histopathol 20:1251–1260PubMedGoogle Scholar
  27. Martelli AM, Gilmour RS, Bertagnolo V, Neri LM, Manzoli L, Cocco L (1992) Nuclear localization and signalling activity of phosphoinositidase Cbeta in Swiss 3T3 cells. Nature 358:242–245PubMedCrossRefGoogle Scholar
  28. Mercurio C, Minucci S, Pelicci PG (2010) Histone deacetylases and epigenetic therapies of hematological malignancies. Pharmacol Res 62:18–34PubMedCrossRefGoogle Scholar
  29. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51PubMedCrossRefGoogle Scholar
  30. Morgan MA, Reuter CW (2006) Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias. Ann Hematol 85:139–163PubMedCrossRefGoogle Scholar
  31. Neff T, Armstrong SA (2009) Chromatin maps, histone modifications and leukemia. Leukemia 23:1243–1251PubMedCrossRefGoogle Scholar
  32. Nyakern M, Tazzari PL, Finelli C et al (2006) Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients. Leukemia 20:230–238PubMedCrossRefGoogle Scholar
  33. O’Carroll SJ, Mitchell MD, Faenza I, Cocco L, Gilmour RS (2009) Nuclear PLCbeta1 is required for 3T3-L1 adipocyte differentiation and regulates expression of the cyclin D3-cdk4 complex. Cell Signal 21:926–935PubMedCrossRefGoogle Scholar
  34. Park S, Chapuis N, Bardet V et al (2008) PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22:1698–1706PubMedCrossRefGoogle Scholar
  35. Perl AE, Kasner MT, Tsai DE et al (2009) A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 15:6732–6739PubMedCrossRefGoogle Scholar
  36. Peruzzi D, Calabrese G, Faenza I et al (2000) Identification and chromosomal localisation by fluorescence in situ hybridisation of human gene of phosphoinositide-specific phospholipase Cbeta1. Biochim Biophys Acta 1484:175–182PubMedCrossRefGoogle Scholar
  37. Quintas-Cardama A, Tong W, Kantarjian H et al (2008) A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia 22:965–970PubMedCrossRefGoogle Scholar
  38. Raj K, John A, Ho A et al (2007) CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 21:1937–1944PubMedCrossRefGoogle Scholar
  39. Schwaller J, Parganas E, Wang D et al (2000) Stat5 is essential for the myelo—and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 6:693–704PubMedCrossRefGoogle Scholar
  40. Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R, Raza A, List AF (2008) Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 26:5943–5949PubMedCrossRefGoogle Scholar
  41. Silverman LR, Mufti GJ (2005) Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat Clin Pract Oncol 2(Suppl 1):12–23CrossRefGoogle Scholar
  42. Srinivasan S, Schiffer CA (2008) Current treatment options and strategies for myelodysplastic syndromes. Expert Opin Pharmacother 9:1667–1678PubMedCrossRefGoogle Scholar
  43. Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123:8–13PubMedCrossRefGoogle Scholar
  44. Suh PG, Park JI, Manzoli L et al (2008) Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 41:415–434PubMedCrossRefGoogle Scholar
  45. Tefferi A, Vardiman JW (2009) Myelodysplastic syndromes. N Engl J Med 361:1872–1885PubMedCrossRefGoogle Scholar
  46. Vardiman JW, Thiele J, Arber DA et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951PubMedCrossRefGoogle Scholar
  47. Xiao W, Ando T, Wang HY, Kawakami Y, Kawakami T (2010) Lyn—and PLCbeta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease. Blood 116:6003–6013PubMedCrossRefGoogle Scholar
  48. Xiao W, Hong H, Kawakami Y et al (2009) Tumor suppression by phospholipase Cbeta3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell 16:161–171PubMedCrossRefGoogle Scholar
  49. Xiao W, Hong H, Kawakami Y, Lowell CA, Kawakami T (2008) Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5. J Clin Invest 118:924–934PubMedGoogle Scholar
  50. Ye K (2005) PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J Cell Biochem 96:463–472PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Sara Mongiorgi
    • 1
  • Matilde Y. Follo
    • 1
  • Cristina Clissa
    • 2
  • Roberto Giardino
    • 3
  • Milena Fini
    • 3
  • Lucia Manzoli
    • 1
  • Giulia Ramazzotti
    • 1
  • Roberta Fiume
    • 1
  • Carlo Finelli
    • 2
  • Lucio Cocco
    • 1
  1. 1.Cellular Signalling Laboratory, Department of Human Anatomical SciencesUniversity of BolognaBolognaItaly
  2. 2.Department of Hematology and Medical Oncology L. e A. SeràgnoliUniversity of BolognaBolognaItaly
  3. 3.Laboratory of Preclinical and Surgical StudiesRizzoli Orthopedic InstituteBolognaItaly

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