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Chronic Lymphocytic Leukemia

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

Leukemia volume 24, pages 2063–2071 (2010)Cite this article

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Abstract

The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.

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References

  1. Ferrarini M, Chiorazzi N . Recent advances in the molecular biology and immunobiology of chronic lymphocytic leukemia. Semin Hematol 2004; 41: 207–223.

    Article  CAS  Google Scholar 

  2. Stevenson FK, Caligaris-Cappio F . Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004; 103: 4389–4395.

    Article  CAS  Google Scholar 

  3. Petlickovski A, Laurenti L, Li X, Marietti S, Chiusolo P, Sica S et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B-cells. Blood 2005; 105: 4820–4827.

    Article  CAS  Google Scholar 

  4. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG . The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood 2008; 111: 846–855.

    Article  CAS  Google Scholar 

  5. Herling M, Patel KA, Weit N, Lilienthal N, Hallek M, Keating MJ et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 2009; 114: 4675–4686.

    Article  CAS  Google Scholar 

  6. Barragán M, Bellosillo B, Campàs C, Colomer D, Pons G, Gil J . Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood 2002; 99: 2969–2976.

    Article  Google Scholar 

  7. Cuní S, Pérez-Aciego P, Pérez-Chacón G, Vargas JA, Sánchez A, Martín-Saavedra FM et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18: 1391–1400.

    Article  Google Scholar 

  8. Hu X, Haney N, Kropp D, Kabore AF, Johnston JB, Gibson SB . Lysophosphatidic acid (LPA) protects primary chronic lymphocytic leukemia cells from apoptosis through LPA receptor activation of the anti-apoptotic protein AKT/PKB. J Biol Chem 2005; 280: 9498–9508.

    Article  CAS  Google Scholar 

  9. Longo PG, Laurenti L, Gobessi S, Petlickovski A, Pelosi M, Chiusolo P et al. The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease. Leukemia 2007; 21: 110–120.

    Article  CAS  Google Scholar 

  10. Ticchioni M, Essafi M, Jeandel PY, Davi F, Cassuto JP, Deckert M et al. Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene 2007; 26: 7081–7091.

    Article  CAS  Google Scholar 

  11. Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV et al. 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 2009; 113: 5549–5557.

    Article  CAS  Google Scholar 

  12. Weinberg JB, Volkheimer AD, Mihovilovic M, Jiang N, Chen Y, Bond K et al. Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia. Leukemia 2008; 22: 2184–2192.

    Article  CAS  Google Scholar 

  13. Balakrishnan K, Burger JA, Wierda WG, Gandhi V . AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 2009; 113: 149–153.

    Article  CAS  Google Scholar 

  14. de Frias M, Iglesias-Serret D, Cosialls AM, Coll-Mulet L, Santidrián AF, González-Gironès DM et al. Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Haematologica 2009; 94: 1698–1707.

    Article  CAS  Google Scholar 

  15. Zhuang J, Hawkins SF, Glenn MA, Lin K, Johnson GG, Carter A et al. Akt is activated in chronic-lymphocytic-leukemia cells and delivers a pro-survival signal: therapeutic potential of Akt inhibition. Haematologica 2010; 95: 110–118.

    Article  CAS  Google Scholar 

  16. Brazil DP, Yang ZZ, Hemmings BA . Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 2004; 29: 233–242.

    Article  CAS  Google Scholar 

  17. Manning BD, Cantley LC . AKT/PKB signaling: navigating downstream. Cell 2007; 129: 1261–1274.

    Article  CAS  Google Scholar 

  18. Shimizu K, Okada M, Takano A, Nagai K . SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus. FEBS Lett 1999; 458: 363–369.

    Article  CAS  Google Scholar 

  19. Gao T, Furnari F, Newton AC . PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 2005; 18: 13–24.

    Article  CAS  Google Scholar 

  20. Brognard J, Sierecki E, Gao T, Newton AC . PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 2007; 25: 917–931.

    Article  CAS  Google Scholar 

  21. Brognard J, Newton AC . PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab 2008; 19: 223–230.

    Article  CAS  Google Scholar 

  22. Gao T, Brognard J, Newton AC . The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem 2008; 283: 6300–6311.

    Article  CAS  Google Scholar 

  23. Shimizu K, Okada M, Nagai K, Fukada Y . Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway. J Biol Chem 2003; 278: 14920–14925.

    Article  CAS  Google Scholar 

  24. Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T . Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene 2009; 28: 994–1004.

    Article  CAS  Google Scholar 

  25. Qiao M, Iglehart JD, Pardee AB . Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res 2007; 67: 5293–5299.

    Article  CAS  Google Scholar 

  26. Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa S et al. Depletion of Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms. J Biol Chem 2009; 284: 22155–22165.

    Article  CAS  Google Scholar 

  27. Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K, Malek SN . Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14. Cancer Res 2008; 68: 1012–1021.

    Article  CAS  Google Scholar 

  28. Hallaert DY, Jaspers A, van Noesel CJ, van Oers MH, Kater AP, Eldering E . c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches. Blood 2008; 112: 5141–5149.

    Article  CAS  Google Scholar 

  29. Shimizu K, Phan T, Mansuy IM, Storm DR . Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory. Cell 2007; 128: 1219–1229.

    Article  CAS  Google Scholar 

  30. Li X, Liu J, Gao T . {beta}-TrCP-mediated ubiquitination and degradation of PHLPP1 is negatively regulated by Akt. Mol Cell Biol 2009; 29: 6192–6205.

    Article  CAS  Google Scholar 

  31. Yuan TL, Cantley LC . PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27: 5497–5510.

    Article  CAS  Google Scholar 

  32. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–1947.

    Article  CAS  Google Scholar 

  33. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.

    Article  CAS  Google Scholar 

  34. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448: 439–444.

    Article  CAS  Google Scholar 

  35. Zenz T, Döhner K, Denzel T, Döhner H, Stilgenbauer S, Bullinger L . Chronic lymphocytic leukaemia and acute myeloid leukaemia are not associated with AKT1 pleckstrin homology domain (E17K) mutations. Br J Haematol 2008; 141: 742–743.

    Article  CAS  Google Scholar 

  36. Mahmoud IS, Sughayer MA, Mohammad HA, Awidi AS, EL-Khateeb MS, Ismail SI . The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias. Br J Cancer 2008; 99: 488–490.

    Article  CAS  Google Scholar 

  37. Marincevic M, Tobin G, Rosenquist R . Infrequent occurrence of PIK3CA mutations in chronic lymphocytic leukemia. Leuk Lymphoma 2009; 50: 829–830.

    Article  CAS  Google Scholar 

  38. Leupin N, Cenni B, Novak U, Hügli B, Graber HU, Tobler A et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol 2003; 121: 97–100.

    Article  CAS  Google Scholar 

  39. Masdehors P, Merle-Béral H, Maloum K, Omura S, Magdelénat H, Delic J . Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood 2000; 96: 269–274.

    CAS  Google Scholar 

  40. Witkowski JM, Zmuda-Trzebiatowska E, Swiercz JM, Cichorek M, Ciepluch H, Lewandowski K et al. Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells. Blood 2002; 100: 1802–1809.

    Article  CAS  Google Scholar 

  41. Agrawal SG, Liu FT, Wiseman C, Shirali S, Liu H, Lillington D et al. Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia. Blood 2008; 111: 2790–2796.

    Article  CAS  Google Scholar 

  42. Ghia P, Chiorazzi N, Stamatopoulos K . Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation. J Intern Med 2008; 264: 549–562.

    Article  CAS  Google Scholar 

  43. Lankester AC, van Schijndel GM, van der Schoot CE, van Oers MH, van Noesel CJ, van Lier RA . Antigen receptor nonresponsiveness in chronic lymphocytic leukemia B cells. Blood 1995; 86: 1090–1097.

    CAS  Google Scholar 

  44. Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK . Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 2007; 109: 4424–4431.

    Article  CAS  Google Scholar 

  45. Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG . ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood 2007; 109: 2032–2039.

    Article  CAS  Google Scholar 

  46. Abrams ST, Lakum T, Lin K, Jones GM, Treweeke AT, Farahani M et al. B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood 2007; 109: 1193–1201.

    Article  CAS  Google Scholar 

  47. Capitani N, Lucherini OM, Sozzi E, Ferro M, Giommoni N, Finetti F et al. Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood 2010; 115: 3726–3736.

    Article  CAS  Google Scholar 

  48. Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci USA 2002; 99: 6955–6960.

    Article  CAS  Google Scholar 

  49. Yan XJ, Albesiano E, Zanesi N, Yancopoulos S, Sawyer A, Romano E et al. B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2006; 103: 11713–11718.

    Article  CAS  Google Scholar 

  50. Masubuchi S, Gao T, O’Neill A, Eckel-Mahan K, Newton AC, Sassone-Corsi P . Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock. Proc Natl Acad Sci USA 2010; 107: 1642–1647.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a Translational Research Grant from the Leukemia & Lymphoma Society (grant R6170-10 to DGE).

Author contributions

MS designed and performed the research, analyzed the data and wrote the paper; LL and MT provided patient material and analyzed the data; MA performed the research; SNM designed the research and analyzed the data; DGE designed the research, analyzed the data and wrote the paper.

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Authors and Affiliations

  1. Department of Molecular Hematology, ICGEB, Campus ‘Adriano Buzzati-Traverso’, Rome, Italy

    M Suljagic & D G Efremov

  2. Department of Hematology, Catholic University Hospital ‘A Gemelli’, Rome, Italy

    L Laurenti & M Tarnani

  3. Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA

    M Alam & S N Malek

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  1. M Suljagic
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Correspondence to D G Efremov.

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Suljagic, M., Laurenti, L., Tarnani, M. et al. Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells. Leukemia 24, 2063–2071 (2010). https://doi.org/10.1038/leu.2010.201

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