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Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia

Leukemia volume 17, pages 1482–1498 (2003)Cite this article

Abstract

Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer agents that specifically target post-translational farnesylation of various proteins that mediate several cellular processes such as signal transduction, growth, differentiation, angiogenesis and apoptosis. These compounds were originally designed to block oncogenic RAS-induced tumor growth by impeding RAS localization to the membrane, but it is now evident that FTIs also affect processing of several other proteins. The need for novel therapies in myeloid leukemia is underscored by the high rate of treatment failure due to high incidences of relapse- and treatment-related toxicities. As RAS deregulation is important in the pathogenesis of myeloid leukemias, targeting of RAS signaling may provide a new therapeutic strategy. Several FTIs (eg BMS-214662, L-778,123, R-115777 and SCH66336) have entered phase I and phase II clinical trials in myeloid leukemias. This review discusses recent clinical results, potential combination therapies, mechanisms of resistance and the clinical challenges of toxicities associated with prenylation inhibitors.

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References

  1. Reuter CWM, Morgan MA, Bergmann L . Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematological malignancies? Blood 2000; 96: 1655–1669.

    CAS  PubMed  Google Scholar 

  2. Hahn SM, Bernhard E, McKenna WG . Farnesyltransferase inhibitors. Semin Oncol 2001; 28: 86–93.

    Article  CAS  PubMed  Google Scholar 

  3. Rosenblatt JD, Rowe JM . Introduction. Semin Hematol 2002; 39: 1–3.

    Article  Google Scholar 

  4. Reuther GW, Der CJ . The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr Opin Cell Biol 2000; 12: 157–165.

    Article  CAS  PubMed  Google Scholar 

  5. Rebollo A, Martinez CA . Ras proteins: recent advances and new functions. Blood 1999; 94: 2971–2980.

    CAS  PubMed  Google Scholar 

  6. Mumby SM . Reversible palmitoylation of signaling proteins. Curr Opin Cell Biol 1997; 9: 148–154.

    Article  CAS  PubMed  Google Scholar 

  7. Wittinghofer A . Signal transduction via Ras. Biol Chem 1998; 379: 933–937.

    CAS  PubMed  Google Scholar 

  8. Marshall CJ . Ras effectors. Curr Opin Cell Biol 1996; 8: 197–204.

    Article  CAS  PubMed  Google Scholar 

  9. Katz ME, McCormick F . Signal transduction from multiple Ras effectors. Curr Opin Genet Dev 1997; 7: 75–79.

    Article  CAS  PubMed  Google Scholar 

  10. Feig LA, Urano T, Cantor S . Evidence for a Ras/Ral signaling cascade. Trends Biochem Sci 1996; 21: 438–441.

    Article  CAS  PubMed  Google Scholar 

  11. Carpenter CL, Cantley LC . Phosphoinositide kinases. Curr Opin Cell Biol 1996; 8: 153–158.

    Article  CAS  PubMed  Google Scholar 

  12. Lee Jr JT, McCubrey JA . The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia 2002; 16: 486–507.

    Article  CAS  PubMed  Google Scholar 

  13. McCubrey JA, Steelman LS, Hoyle PE, Blalock WL, Weinstein-Oppenheimer C, Franklin RA et al. Differential abilities of activated Raf oncoproteins to abrogate cytokine dependency, prevent apoptosis and induce autocrine growth factor synthesis in human hematopoietic cells. Leukemia 1998; 12: 1903–1929.

    Article  CAS  PubMed  Google Scholar 

  14. Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA et al. Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs. Leukemia 1999; 13: 1109–1166.

    Article  CAS  PubMed  Google Scholar 

  15. Blalock WL, Moye PW, Chang F, Pearce M, Steelman LS, McMahon M et al. Combined effects of aberrant MEK1 activity and BCL2 overexpression on relieving the cytokine dependency of human and murine hematopoietic cells. Leukemia 2000; 14: 1080–1096.

    Article  CAS  PubMed  Google Scholar 

  16. Blalock WL, Pearce M, Steelman LS, Franklin RA, McCarthy SA, Cherwinski H et al. A conditionally-active form of MEK1 results in autocrine transformation of human and mouse hematopoietic cells. Oncogene 2000; 19: 526–536.

    Article  CAS  PubMed  Google Scholar 

  17. Hoyle PE, Moye PW, Steelman LS, Blalock WL, Franklin RA, Pearce M et al. Differential abilities of the Raf family of protein kinases to abrogate cytokine dependency and prevent apoptosis in murine hematopoietic cells by a MEK1-dependent mechanism. Leukemia 2000; 14: 642–656.

    Article  CAS  PubMed  Google Scholar 

  18. Moye PW, Blalock WL, Hoyle PE, Chang F, Franklin RA, Weinstein-Oppenheimer C et al. Synergy between Raf and BCL2 in abrogating the cytokine dependency of hematopoietic cells. Leukemia 2000; 14: 1060–1079.

    Article  CAS  PubMed  Google Scholar 

  19. Weinstein-Oppenheimer C, Steelman LS, Algate PA, Blalock WL, Burrows C, Hoyle PE et al. Effects of deregulated Raf activation on integrin, cytokine-receptor expression and the induction of apoptosis in hematopoietic cells. Leukemia 2000; 14: 1921–1938.

    Article  CAS  PubMed  Google Scholar 

  20. Blalock WL, Pearce M, Chang F, Lee JT, Pohnert SC, Burrows C et al. Effects of inducible MEK1 activation on the cytokine dependency of lymphoid cells. Leukemia 2001; 15: 794–807.

    Article  CAS  PubMed  Google Scholar 

  21. White MK, McCubrey JA . Suppression of apoptosis: role in cell growth and neoplasia. Leukemia 2001; 15: 1011–1021.

    Article  CAS  PubMed  Google Scholar 

  22. Bos JL . RAS oncogenes in human cancer: a review. Cancer Res 1989; 49: 4682–4689.

    CAS  PubMed  Google Scholar 

  23. Clark GJ, Der CJ . Ras proto-oncogene activation in human malignancy. In: Garrett CT, Sell S (eds), Cellular Cancer Markers. Totowa, New Jersey: Humana Press, 1995, pp 17–52.

    Chapter  Google Scholar 

  24. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmuller L, Lautwein A, Schmitz F et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997; 277: 333–338.

    Article  CAS  PubMed  Google Scholar 

  25. Lin SR, Tsai JH, Yang YC, Lee SC . Mutations of K-Ras oncogene in human adrenal tumors in Taiwan. Br J Cancer 1998; 77: 1060–1065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lin SR, Hsu CH, Tsai JH, Wang JY, Hsieh TJ, Wu CH . Decreased GTPase activity of K-Ras deriving from human functional adrenocortical tumours. Br J Cancer 2000; 82: 1035–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sprang SR . G protein mechanisms: insights from structural analysis. Ann Rev Biochem 1997; 66: 639–678.

    Article  CAS  PubMed  Google Scholar 

  28. Byrne JL, Marshall CJ . The molecular pathophysiology of myeloid leukaemias: Ras revisited. Br J Haematol 1998; 100: 256–264.

    Article  CAS  PubMed  Google Scholar 

  29. Sawyers CL, Denny CT . Chronic myelomonocytic leukemia: Tel-a-kinase what its all about. Cell 1994; 77: 171–173.

    Article  CAS  PubMed  Google Scholar 

  30. Beaupre DM, Kurzrock R . RAS and leukemia: from basic mechanisms to gene-directed therapy. J Clin Oncol 1999; 17: 1071–1079.

    Article  CAS  PubMed  Google Scholar 

  31. Tobal K, Pagliuca A, Bhatt B, Bailey N, Layton DM, Mufti GJ . Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia. Leukemia 1990; 4: 486–489.

    CAS  PubMed  Google Scholar 

  32. Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H et al. Constitutively activating mutations of c-Kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood 1995; 85: 790–798.

    CAS  PubMed  Google Scholar 

  33. Nakata Y, Kimura A, Katoh O, Kawaishi K, Hyodo H, Abe K et al. c-Kit point mutation of extracellular domain in patients with myeloproliferative disorders. Br J Haematol 1995; 91: 661–663.

    Article  CAS  PubMed  Google Scholar 

  34. Dosil M, Wang S, Lemischka IR . Mitogenic signaling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol Cell Biol 1993; 13: 6572–6585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-Ras gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.

    CAS  PubMed  Google Scholar 

  36. Golub T, Barker G, Lovett M, Gilliland D . Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316.

    Article  CAS  PubMed  Google Scholar 

  37. Jousset C, Carron C, Boureux A, Quang CT, Oury C, Dusanter-Fourt I et al. A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFRβ oncoprotein. EMBO J 1997; 16: 69–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Papadopoulos P, Raidge SA, Boucher CA, Stocking C, Wiedemann LM . The novel activation of abl by fusion to an ets-related gene, tel. Cancer Res 1995; 55: 34–38.

    CAS  PubMed  Google Scholar 

  39. Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J, Bohlander SK et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol 1996; 16: 4107–4116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zou X, Calame K . Signaling pathways activated by oncogenic forms of Abl tyrosine kinase. J Biol Chem 1999; 274: 18141–18144.

    Article  CAS  PubMed  Google Scholar 

  41. Voss J, Posern G, Hannemann JR, Wiedemann LM, Turhan AG, Poirel H et al. The leukaemic oncoproteins BCR-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signaling pathways. Oncogene 2000; 19: 1684–1690.

    Article  CAS  PubMed  Google Scholar 

  42. DeClue JE, Papageorge AG, Fletcher JA, Diehl SR, Ratner N, Vass WC et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 1992; 69: 265–273.

    Article  CAS  PubMed  Google Scholar 

  43. Kalra R, Paderanga DC, Olson K, Shannon KM . Genetic analysis is consistent with the hypothesis that NF-1 limits myeloid cell growth through p21ras. Blood 1994; 84: 3435–3439.

    CAS  PubMed  Google Scholar 

  44. Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 1996; 12: 144–148.

    Article  CAS  PubMed  Google Scholar 

  45. Largaespada DA, Brannan CI, Jenkins NA, Copeland NG . NF-1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia. Nat Genet 1996; 12: 137–143.

    Article  CAS  PubMed  Google Scholar 

  46. Largaespada DA . Genetic heterogeneity in acute myeloid leukemia: maximizing information flow from MuLV mutagenesis studies. Leukemia 2000; 14: 1174–1184.

    Article  CAS  PubMed  Google Scholar 

  47. Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 1997; 11: 1442–1446.

    Article  CAS  PubMed  Google Scholar 

  48. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 1997; 11: 1605–1609.

    Article  CAS  PubMed  Google Scholar 

  49. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998; 12: 1333–1337.

    Article  CAS  PubMed  Google Scholar 

  50. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE . Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia 2000; 14: 675–683.

    Article  CAS  PubMed  Google Scholar 

  51. Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002; 16: 2185–2189.

    Article  CAS  PubMed  Google Scholar 

  52. Iwai T, Yokota S, Nakao M, Okamoto T, Taniwaki M, Onodera N et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia 1999; 13: 38–43.

    Article  CAS  PubMed  Google Scholar 

  53. Xu F, Taki T, Eguchi M, Kamada N, Ishii E, Endo M et al. Tandem duplication of the FLT3 gene is infrequent in infant acute leukemia. Japan Infant Leukemia Study Group. Leukemia 2000; 14: 945–957.

    Article  CAS  PubMed  Google Scholar 

  54. Rubnitz JE, Raimondi SC, Halbert AR, Tong X, Srivastava DK, Razzouk BI et al. Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: a single institution's experience. Leukemia 2002; 16: 2072–2077.

    Article  CAS  PubMed  Google Scholar 

  55. Zhao M, Kiyoi H, Yamamoto Y, Ito M, Towatari M, Omura S et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 2000; 14: 374–348.

    Article  CAS  PubMed  Google Scholar 

  56. Tse KF, Allebach J, Levis M, Smith BD, Bohmer FD, Small D . Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 2002; 16: 2027–2036.

    Article  CAS  PubMed  Google Scholar 

  57. Minami Y, Kiyoi H, Yamamoto Y, Yamamoto K, Ueda R, Saito H et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 2002; 16: 1535–1540.

    Article  CAS  PubMed  Google Scholar 

  58. Rohrschneider LR, Bourette RP, Lioubin MN, Algate PA, Myles GM, Carlberg K . Growth and differentiation signals regulated by the M-CSF receptor. Mol Reprod Dev 1997; 46: 96–103.

    Article  CAS  PubMed  Google Scholar 

  59. Hunter T . Oncoprotein networks. Cell 1997; 88: 333–346.

    Article  CAS  PubMed  Google Scholar 

  60. Kurzrock R, Gutterman JU, Talpaz M . The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 1988; 319: 990–998.

    Article  CAS  PubMed  Google Scholar 

  61. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM . The biology of chronic myeloid leukemia. N Engl J Med 1999; 341: 164–172.

    Article  CAS  PubMed  Google Scholar 

  62. Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S . Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 1994; 83: 2248–2254.

    CAS  PubMed  Google Scholar 

  63. Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T et al. Nf1 and Gmcsf interact in myeloid leukemogenesis. Mol Cell 2000; 5: 189–195.

    Article  CAS  PubMed  Google Scholar 

  64. Hotte SJ, Hirte HW . BAY 43-9006: early clinical data in patients with advanced solid malignancies. Curr Pharm Des 2002; 8: 2249–2253.

    Article  CAS  PubMed  Google Scholar 

  65. Sebti SM, Hamilton AD . Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 2000; 19: 6584–6493.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang FL, Casey PJ . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996; 65: 241–269.

    Article  CAS  PubMed  Google Scholar 

  67. Sinensky M . Recent advances in the study of prenylated proteins. Biochim Biophys Acta 2000; 1484: 93–106.

    Article  CAS  PubMed  Google Scholar 

  68. Park HW, Boduluri SR, Moomaw JF, Casey PJ, Beese LS . Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science 1997; 275: 1800–1804.

    Article  CAS  PubMed  Google Scholar 

  69. Liang PH, Ko TP, Wang AH . Structure, mechanism and function of prenyltransferases. Eur J Biochem 2002; 269: 3339–3354.

    Article  CAS  PubMed  Google Scholar 

  70. Prior IA, Hancock JF . Compartmentalization of Ras proteins. J Cell Sci 2001; 114: 1603–1608.

    CAS  PubMed  Google Scholar 

  71. Gibbs JB, Oliff A . The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 1997; 37: 143–166.

    Article  CAS  PubMed  Google Scholar 

  72. Heimbrook DC, Oliff A . Therapeutic intervention and signaling. Curr Opin Cell Biol 1998; 10: 284–288.

    Article  CAS  PubMed  Google Scholar 

  73. Crul M, de Klerk GJ, Beijnen JH, Schellens JH . Ras biochemistry and farnesyl transferase inhibitors: a literature survey. Anticancer Drugs 2001; 12:163–184.

    Article  CAS  PubMed  Google Scholar 

  74. Rowinsky EK, Windle JJ, Von Hoff DD . Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17: 3631–3652.

    Article  CAS  PubMed  Google Scholar 

  75. Tamanoi F, Gau C-L, Jiang C, Edamatsu H, Kato-Stankiewicz J . Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells. Cell Mol Life Sci 2001; 58: 1636–1649.

    Article  CAS  PubMed  Google Scholar 

  76. Crespo NC, Ohkanda J, Yen TJ, Hamilton AD, Sebti SM . The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 2001; 276: 16161–16167.

    Article  CAS  PubMed  Google Scholar 

  77. Ashar HR, James L, Gray K, Carr D, Black S, Armstrong L et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem 2000; 275: 30451–30457.

    Article  CAS  PubMed  Google Scholar 

  78. Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 2000; 20: 139–148.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kim KW, Chung HH, Chung CW, Kim IK, Miura M, Wang S et al. Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: cleavage of the common alpha subunit during apoptosis. Oncogene 2001; 20: 358–366.

    Article  CAS  PubMed  Google Scholar 

  80. Hall A . Rho GTPases and the actin cytoskeleton. Science 1998; 279: 509–514.

    CAS  PubMed  Google Scholar 

  81. Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature 2002; 420: 629–635.

    Article  CAS  PubMed  Google Scholar 

  82. Bishop AL, Hall A . Rho GTPases and their effector proteins. Biochem J 2000; 348: 241–255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ridley AJ . Rho family proteins: coordinating cell responses. Trends Cell Biol 2001; 11: 471–477.

    Article  CAS  PubMed  Google Scholar 

  84. Wittmann T, Waterman-Storer CM . Cell motility: can Rho GTPases and microtubules point the way? J Cell Sci 2001; 114: 3795–3803.

    CAS  PubMed  Google Scholar 

  85. Prendergast GC . Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects. Curr Opin Cell Biol 2000; 12: 166–173.

    Article  CAS  PubMed  Google Scholar 

  86. Liu AX, Du W, Liu JP, Jessell TM, Prendergast GC . RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol Cell Biol 2000; 20: 6105–6113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Du W, Prendergast GC . Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res 1999; 59: 5492–5496.

    CAS  PubMed  Google Scholar 

  88. Du W, Lebowitz PF, Prendergast GC . Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999; 19: 1831–1840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM . Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem 2000; 275: 17974–17978.

    Article  CAS  PubMed  Google Scholar 

  90. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM . Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 1997; 272: 14093–14097.

    Article  CAS  PubMed  Google Scholar 

  91. Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997; 272: 14459–14464.

    Article  CAS  PubMed  Google Scholar 

  92. Mazet JL, Padieu M, Osman H, Maume G, Mailliet P, Dereu N et al. Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase-1 inhibitor GGTI-298 disrupts MAP kinase activation and G(1)-S transition in Ki-Ras-overexpressing transformed adrenocortical cells. FEBS Lett 1999; 460: 235–240.

    Article  CAS  PubMed  Google Scholar 

  93. Di Paolo A, Danesi R, Caputo S, Macchia M, Lastella M, Boggi U et al. Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells. Br J Cancer 2001; 84: 1535–1543.

    Article  CAS  PubMed  Google Scholar 

  94. Lobell RB, Omer CA, Abrams MT, Bhimnathwala HG, Brucker MJ, Buser CA et al. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res 2001; 61: 8758–8768.

    CAS  PubMed  Google Scholar 

  95. Lobell RB, Liu D, Buser CA, Davide JP, DePuy E, Hamilton K et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 2002; 1: 747–758.

    CAS  PubMed  Google Scholar 

  96. Morgan MA, Wegner J, Aydilek E, Ganser A, Reuter CWM . Synergistic cytotoxic effects in myeloid leukemia cells upon co-treatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors. Leukemia (in press).

  97. Huber HE, Robinson RG, Watkins A, Nahas DD, Abrams MT, Buser CA et al. Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors. J Biol Chem 2001; 276: 24457–24465.

    Article  CAS  PubMed  Google Scholar 

  98. Lerner EC, Qian Y, Hamilton AD, Sebti SM . Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor. J Biol Chem 1995; 270: 26770–26773.

    Article  CAS  PubMed  Google Scholar 

  99. Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM . Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 1997; 15: 1283–1288.

    Article  CAS  PubMed  Google Scholar 

  100. Qian Y, Vogt A, Vasudevan A, Sebti SM, Hamilton AD . Selective inhibition of type-I geranylgeranyltransferase in vitro and in whole cells by CAAL peptidomimetics. Bioorg Med Chem 1998; 6: 293–299.

    Article  CAS  PubMed  Google Scholar 

  101. Vasudevan A, Qian Y, Vogt A, Blaskovich MA, Ohkanda J, Sebti SM et al. Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I. J Med Chem 1999; 42: 1333–1340.

    Article  CAS  PubMed  Google Scholar 

  102. Buser CA, Dinsmore CJ, Fernandes C, Greenberg I, Hamilton K, Mosser SD et al. High-performance liquid chromatography/mass spectrometry characterization of Ki4B-Ras in PSN-1 cells treated with the prenyltransferase inhibitor L-778,123. Anal Biochem 2001; 290: 126–137.

    Article  CAS  PubMed  Google Scholar 

  103. Sun J, Qian Y, Hamilton AD, Sebti SM . Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 1998; 16: 1467–1473.

    Article  CAS  PubMed  Google Scholar 

  104. Sun J, Blaskovich MA, Knowles D, Qian Y, Ohkanda J, Bailey RD et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 1999; 59: 4919–4926.

    CAS  PubMed  Google Scholar 

  105. Miquel K, Pradines A, Sun J, Qian Y, Hamilton AD, Sebti SM et al. GGTI-298 induces G0–G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res 1997; 57: 1846–1850.

    CAS  PubMed  Google Scholar 

  106. Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM . The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem 1997; 272: 27224–27229.

    Article  CAS  PubMed  Google Scholar 

  107. Adnane J, Bizouarn FA, Qian Y, Hamilton AD, Sebti SM . p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor beta- and Sp1-responsive element: involvement of the small GTPase rhoA. Mol Cell Biol 1998; 18: 6962–6970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Thompson GR, Naoumova RP . Novel lipid-regulating drugs. Expert Opin Invest Drugs 2000; 9: 2619–2628.

    Article  CAS  Google Scholar 

  109. Wong WW, Dimitroulakos J, Minden MD, Penn LZ . HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 2002; 16: 508–519.

    Article  CAS  PubMed  Google Scholar 

  110. Jakobisiak M, Bruno S, Skierski JS, Darzynkiewicz Z . Cell cycle-specific effects of lovastatin. Proc Natl Acad Sci USA 1991; 88: 3628–3632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Keyomarsi K, Sandoval L, Band V, Pardee AB . Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 1991; 51: 3602–3609.

    CAS  PubMed  Google Scholar 

  112. Gray-Bablin J, Rao S, Keyomarsi K . Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion. Cancer Res 1997; 57: 604–609.

    CAS  PubMed  Google Scholar 

  113. Lee SJ, Ha MJ, Lee J, Nguyen P, Choi YH, Pirnia F et al. Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells. J Biol Chem 1998; 273: 10618–10623.

    Article  CAS  PubMed  Google Scholar 

  114. Rao S, Lowe M, Herliczek TW, Keyomarsi K . Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene 1998; 17: 2393–2402.

    Article  CAS  PubMed  Google Scholar 

  115. Wachtershauser A, Akoglu B, Stein J . HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Carcinogenesis 2001; 22: 1061–1067.

    Article  CAS  PubMed  Google Scholar 

  116. Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD, Penn LZ . Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. Leukemia Lymphoma 2000; 40: 167–178.

    Article  CAS  PubMed  Google Scholar 

  117. Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ . Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin. Clin Cancer Res 2001; 7: 2067–2075.

    CAS  PubMed  Google Scholar 

  118. Newman A, Clutterbuck RD, Powles RL, Millar JL . Selective inhibition of primary acute myeloid leukaemia cell growth by lovastatin. Leukemia 1994; 8: 274–280.

    CAS  PubMed  Google Scholar 

  119. Newman A, Clutterbuck RD, DeLord C, Powles RL, Catovsky D, Millar JL . The sensitivity of leukemic bone marrow to simvastatin is lost at remission: a potential purging agent for autologous bone marrow transplantation. J Invest Med 1995; 43: 269–274.

    CAS  Google Scholar 

  120. Newman A, Clutterbuck RD, Powles RL, Catovsky D, Millar JL . A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors. Leukemia Lymphoma 1997; 24: 533–537.

    Article  CAS  PubMed  Google Scholar 

  121. Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger H, Freedman MH et al. Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 1999; 93: 1308–1318.

    CAS  PubMed  Google Scholar 

  122. Wang IK, Lin-Shiau SY, Lin JK . Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. Pharmacol Toxicol 2000; 86: 83–91.

    Article  CAS  PubMed  Google Scholar 

  123. Marcelli M, Cunningham GR, Haidacher SJ, Padayatty SJ, Sturgis L, Kagan C et al. Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP. Cancer Res 1998; 58: 76–83.

    CAS  PubMed  Google Scholar 

  124. Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn LZ . Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia 2001; 15: 1398–1407.

    Article  CAS  PubMed  Google Scholar 

  125. Lishner M, Bar-Sef A, Elis A, Fabian I . Effect of simvastatin alone and in combination with cytosine arabinoside on the proliferation of myeloid leukemia cell lines. J Invest Med 2001; 49: 319–324.

    Article  CAS  Google Scholar 

  126. Stirewalt DL, Appelbaum FR, Willman CL, Zager RA, Banker DE . Mevastatin can increase toxicity in primary AMLs exposed to standard therapeutic agents, but statin efficacy is not simply associated with ras hotspot mutations or overexpression. Leukemia Res 2003; 27: 133–145.

    Article  CAS  Google Scholar 

  127. Clutterbuck RD, Millar BC, Powles RL, Newman A, Catovsky D, Jarman M et al. Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice. Br J Haematol 1998; 102: 522–527.

    Article  CAS  PubMed  Google Scholar 

  128. Minden MD, Dimitroulakos J, Nohynek D, Penn LZ . Lovastatin induced control of blast cell growth in an elderly patient with acute myeloblastic leukemia. Leukemia Lymphoma 2001; 40: 659–662.

    Article  CAS  PubMed  Google Scholar 

  129. Li HY, Appelbaum FR, Willman CL, Zager RA, Banker DE . Cholesterol modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses. Blood 2003; 101: 3628–3634.

    Article  CAS  PubMed  Google Scholar 

  130. Haluska P, Dy GK, Adjei AA . Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer 2002; 38: 1685–1700.

    Article  CAS  PubMed  Google Scholar 

  131. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131–137.

    CAS  PubMed  Google Scholar 

  132. Kelland LR, Smith V, Valenti M, Patterson L, Clarke PA, Detre S et al. Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 2001; 7: 3544–3550.

    CAS  PubMed  Google Scholar 

  133. Zujewski J, Horak ID, Bol CJ, Woestenborghs R, Bowden C, End DW et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2000; 18: 927–941.

    Article  CAS  PubMed  Google Scholar 

  134. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001; 97: 3361–3369.

    Article  CAS  PubMed  Google Scholar 

  135. Punt CJ, van Maanen L, Bol CJ, Seifert WF, Wagener DJ . Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors. Anticancer Drugs 2001; 12: 193–197.

    Article  CAS  PubMed  Google Scholar 

  136. Crul M, de Klerk GJ, Swart M, van't Veer LJ, de Jong D, Boerrigter L et al. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2002; 20: 2726–2735.

    Article  CAS  PubMed  Google Scholar 

  137. Morgan MA, Dolp O, Reuter CW . Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood 2001; 97: 1823–1834.

    Article  CAS  PubMed  Google Scholar 

  138. Cortes JE, Albitar M, Thomas D, Giles F, Kurzrock R, Thibault A et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematological malignancies. Blood 2003; 101: 1692–1697.

    Article  CAS  PubMed  Google Scholar 

  139. Bishop WR, Bond R, Petrin J, Wang L, Patton R, Doll R et al. Novel tricyclic inhibitors of farnesyl protein transferase. J Biol Chem 1995; 270: 30611–30618.

    Article  CAS  PubMed  Google Scholar 

  140. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 1998; 58: 4947–4956.

    CAS  PubMed  Google Scholar 

  141. Petit T, Izbicka E, Lawrence RA, Bishop WR, Weitman S, Von Hoff DD . Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. Ann Oncol 1999; 10: 449–453.

    Article  CAS  PubMed  Google Scholar 

  142. Liu M, Bishop WR, Nielsen LL, Bryant MS, Kirschmeier P . Orally bioavailable farnesyltransferase inhibitors as anticancer agents in transgenic and xenograft models. Methods Enzymol 2001; 333: 306–318.

    Article  CAS  PubMed  Google Scholar 

  143. Shi B, Yaremko B, Hajian G, Terracina G, Bishop WR, Liu M et al. The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo. Cancer Chemother Pharmacol 2000; 46: 387–393.

    Article  CAS  PubMed  Google Scholar 

  144. Adjei AA, Davis JN, Bruzek LM, Erlichman C, Kaufmann SH . Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin Cancer Res 2001; 7: 1438–1445.

    CAS  PubMed  Google Scholar 

  145. Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 2001; 97: 1404–1412.

    Article  CAS  PubMed  Google Scholar 

  146. Reichert A, Heisterkamp N, Daley GQ, Groffen J . Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood 2001; 97: 1399–1403.

    Article  CAS  PubMed  Google Scholar 

  147. Hoover RR, Mahon FX, Melo JV, Daley GQ . Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 2002; 100: 1068–1071.

    Article  CAS  PubMed  Google Scholar 

  148. Brodsky AL, Daley GQ, Hoover RR, Carr D, Kirschmeier P . Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line. Blood 2003; 101: 2070.

    Article  CAS  PubMed  Google Scholar 

  149. Adjei AA, Erlichman C, Davis JN, Cutler DL, Sloan JA, Marks RS et al. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000; 60: 1871–1877.

    CAS  PubMed  Google Scholar 

  150. Eskens FA, Awada A, Cutler DL, de Jonge MJ, Luyten GP, Faber MN et al. Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors. J Clin Oncol 2001; 19: 1167–1175.

    Article  CAS  PubMed  Google Scholar 

  151. Hunt JT, Ding CZ, Batorsky R, Bednarz M, Bhide R, Cho Y et al. Discovery of (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 2000; 43: 3587–3595.

    Article  CAS  PubMed  Google Scholar 

  152. Rose WC, Lee FY, Fairchild CR, Lynch M, Monticello T, Kramer RA, Manne V . Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. Cancer Res 2001; 61: 7507–7517.

    CAS  PubMed  Google Scholar 

  153. Britten CD, Rowinsky EK, Soignet S, Patnaik A, Yao SL, Deutsch P et al. A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies. Clin Cancer Res 2001; 7: 3894–3903.

    CAS  PubMed  Google Scholar 

  154. Hahn SM, Bernhard EJ, Regine W, Mohiuddin M, Haller DG, Stevenson JP et al. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 2002; 8: 1065–1072.

    CAS  PubMed  Google Scholar 

  155. Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM . Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 1995; 55: 5310–5314.

    CAS  PubMed  Google Scholar 

  156. James G, Goldstein JL, Brown MS . Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc Natl Acad Sci USA 1996; 93: 4454–4458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995; 1: 792–797.

    Article  CAS  PubMed  Google Scholar 

  158. Mangues R, Corral T, Kohl NE, Symmans WF, Lu S, Malumbres M et al. Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res 1998; 58: 1253–1259.

    CAS  PubMed  Google Scholar 

  159. Omer CA, Chen Z, Diehl RE, Conner MW, Chen HY, Trumbauer ME et al. Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Cancer Res 2000; 60: 2680–2688.

    CAS  PubMed  Google Scholar 

  160. Zhang FL, Kirschmeier P, Carr D, James L, Bond RW, Wang L et al. Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem 1997; 272: 10232–10239.

    Article  CAS  PubMed  Google Scholar 

  161. Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ . Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 1992; 89: 6403–6407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Prendergast GC, Davide JP, Lebowitz PF, Wechsler-Reya R, Kohl NE . Resistance of a variant ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibitors. Cancer Res 1996; 56: 2626–2632.

    CAS  PubMed  Google Scholar 

  163. Del Villar K, Urano J, Guo L, Tamanoi F . A mutant form of human protein farnesyltransferase exhibits increased resistance to farnesyltransferase inhibitors. J Biol Chem 1999; 274: 27010–27017.

    Article  CAS  PubMed  Google Scholar 

  164. Smith V, Rowlands MG, Barrie E, Workman P, Kelland LR . Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line. Clin Cancer Res 2002; 8: 2002–2009.

    CAS  PubMed  Google Scholar 

  165. Hu W, Wu W, Yeung SC, Freedman RS, Kavanagh JJ, Verschraegen CF . Increased expression of heat shock protein 70 in adherent ovarian cancer and mesothelioma following treatment with manumycin, a farnesyl transferase inhibitor. Anticancer Res 2002; 22: 665–672.

    CAS  PubMed  Google Scholar 

  166. Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.Cancer Res 1995; 55: 5302–5309.

    CAS  PubMed  Google Scholar 

  167. Wang E, Casciano CN, Clement RP, Johnson WW . The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res 2001; 61: 7525–7529.

    CAS  PubMed  Google Scholar 

  168. Bos JL, Verlaan-de-Vries M, van-der-Eb AJ, Janssen JW, Delwel R, Lowenberg B et al. Mutations in N-Ras predominate in acute myeloid leukemia. Blood 1987; 69: 1237–1241.

    CAS  PubMed  Google Scholar 

  169. Janssen J, Steenvoorden A, Lyons J, Anger B, Bohlke JU, Bos JL et al. Ras gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. Proc Natl Acad Sci USA 1987; 84: 9228–9232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schakel U et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol 2001; 112: 300–307.

    Article  CAS  PubMed  Google Scholar 

  171. Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ . Analysis of Ras gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucteotide probes. Proc Natl Acad Sci USA 1988; 85: 1629–1633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Vogelstein B, Civin CI, Preisinger AC, Krischer JP, Steuber P, Ravindranath Y et al. Ras gene mutations in childhood acute myeloid leukemia: a pediatric oncology group study. Genes Chromosomer Cancer 1990; 2: 159–162.

    Article  CAS  Google Scholar 

  173. Neri A, Knowes DM, Greco A, McCormick F, Dalla-Favera R . Analysis of Ras oncogene mutations in human lymphoid malignancies. Proc Natl Acad Sci USA 1988; 85: 9268–9272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Browett PJ, Yaxley JC, Norton JD . Activation of Harvey ras oncogene by mutation at codon 12 is very rare in hematopoietic malignancies. Leukemia 1989; 3: 86–88.

    CAS  PubMed  Google Scholar 

  175. Browett PJ, Norton JD . Analysis of RAS gene mutations and methylation state in human leukemias. Oncogene 1989; 4: 1029–1036.

    CAS  PubMed  Google Scholar 

  176. Padua RA, Carter G, Hughes D, Gow J, Farr C, Oscier D et al. Ras mutations in myelodysplasia detected by amplification, oligonucleotide hybridization and transformation. Leukemia 1988; 2: 503–510.

    CAS  PubMed  Google Scholar 

  177. Hirsch-Ginsberg C, LeMaistre AC, Kantarjian H, Talpaz M, Cork A, Freireich EJ et al. Ras mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia. Blood 1990; 76: 1214–1219.

    CAS  PubMed  Google Scholar 

  178. Neri A, Murphy JP, Cro L, Ferrero D, Tarella C, Baldini L et al. Ras oncogene mutation in multiple myeloma. J Exp Med 1989; 170: 1715–1725.

    Article  CAS  PubMed  Google Scholar 

  179. Tanaka K, Takechi M, Asaoku H, Dohy H, Kamada N . A high frequency of N-Ras oncogene mutations in multiple myeloma. Int J Hematol 1992; 56: 119–127.

    CAS  PubMed  Google Scholar 

  180. Corradini P, Ladetto M, Voena C, Palumbo A, Inghirami G, Knowles DM et al. Mutational activation of N- and K-RAS oncogenes in plasma cell dyscrasias. Blood 1993; 81: 2708–2713.

    CAS  PubMed  Google Scholar 

  181. Hallek M, Leif Bergsagel P, Anderson KC . Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998; 91: 3–21.

    CAS  PubMed  Google Scholar 

  182. Bezieau S, Devilder MC, Avet-Loiseau H, Mellerin MP, Puthier D, Pennarun E et al. High incidence on N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat 2001; 18: 212–224.

    Article  CAS  PubMed  Google Scholar 

  183. Kalakonda N, Rothwell DG, Scarffe JH, Norton JD . Detection of N-Ras codon 61 mutations in subpopulations of tumor cells in multiple myeloma at presentation. Blood 2001; 98: 1555–1560.

    Article  CAS  PubMed  Google Scholar 

  184. Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T et al. Ras, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia 1998; 12: 887–892.

    Article  CAS  PubMed  Google Scholar 

  185. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595.

    Article  CAS  PubMed  Google Scholar 

  186. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

    Article  CAS  PubMed  Google Scholar 

  187. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT . Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001; 113: 983–938.

    Article  CAS  PubMed  Google Scholar 

  188. Gilliland DG, Griffin JD . Role of FLT3 in leukemia. Curr Opin Hematol 2002; 9: 274–281.

    Article  PubMed  Google Scholar 

  189. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    Article  CAS  PubMed  Google Scholar 

  190. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA 1995; 92: 10560–10564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Buttner C, Henz BM, Welker P, Sepp NT, Grabbe J . Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavior. J Invest Dermatol 1998; 111: 1227–1231.

    Article  CAS  PubMed  Google Scholar 

  192. Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P et al. The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood 1999; 94: 4370–4373.

    CAS  PubMed  Google Scholar 

  193. Iijima Y, Ito T, Oikawa T, Eguchi M, Euchi-Ishimae M, Kamada N et al. A new ETV/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Blood 2000; 95: 2126–2131.

    CAS  PubMed  Google Scholar 

  194. Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Sato Y et al. Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 1999; 93: 1355–1363.

    CAS  PubMed  Google Scholar 

  195. Liu Q, Schwaller J, Kutok J, Cain D, Aster JC, Williams IR et al. Signal transduction and transforming properties of the TEL-TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia. EMBO J 2000; 19: 1827–1838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H . Fusion of the platelet-derived growth factor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 1997; 90: 4271–4277.

    CAS  PubMed  Google Scholar 

  197. Elmberger PG, Lozano MD, Weisenburger DD, Sanger W, Chan WC . Transcripts of the npm-alk fusion gene in anaplastic large cell lymphoma Hodgkin's disease, and reactive lymphoid lesions. Blood 1995; 86: 3517–3521.

    CAS  PubMed  Google Scholar 

  198. Waggott W, Lo YM, Bastard C, Gatter KC, Leroux D, Mason DY et al. Detection of NPM-ALK DNA rearrangement in CD30 positive anaplastic large cell lymphoma. Br J Haematol 1995; 89: 905–907.

    Article  CAS  PubMed  Google Scholar 

  199. Zou X, Calame K . Signaling pathways activated by oncogenic forms of Abl tyrosine kinase. J Biol Chem 1999; 274: 18141–18144.

    Article  CAS  PubMed  Google Scholar 

  200. Demiroglu A, Steer E, Heath C, Taylor K, Bentley M, Allen S et al. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 2001; 98: 3778–3783.

    Article  CAS  PubMed  Google Scholar 

  201. Ross TS, Bernard OA, Berger R, Gilliland DG . Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 1998; 91: 4419–4426.

    CAS  PubMed  Google Scholar 

  202. Ross TS, Gilliland DG . Transforming properties of the Huntingtin interacting protein 1/platelet-derived growth factor beta receptor fusion protein. J Biol Chem 1999; 274: 22328–22336.

    Article  CAS  PubMed  Google Scholar 

  203. Sohal J, Chase A, Mould S, Corcoran M, Oscier D, Iqbal S et al. Identification of four new translocations involving FGFR1 in myeloid disorders. Genes Chromosomes Cancer 2001; 32: 155–163.

    Article  CAS  PubMed  Google Scholar 

  204. Macdonald D, Reiter A, Cross NC . The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002; 107: 101–107.

    Article  CAS  PubMed  Google Scholar 

  205. Tycko B, Smith SD, Sklar J . Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia. J Exp Med 1991; 174: 867–873.

    Article  CAS  PubMed  Google Scholar 

  206. Burnett RC, Thirman MJ, Rowley JD, Diaz MO . Molecular analysis of the T-cell acute lymphoblastic leukemia-associated t(1;7)(p34;q34) that fuses LCK and TCRB. Blood 1994; 84: 1232–1236.

    CAS  PubMed  Google Scholar 

  207. Lacronique V, Boureux A, Monni R, Dumon S, Mauchauffe M, Mayeux P et al. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood 2000; 95: 2076–2083.

    CAS  PubMed  Google Scholar 

  208. Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M et al. Homozygous inactivation of the NF-1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 1997; 336: 1713–1720.

    Article  CAS  PubMed  Google Scholar 

  209. Farnsworth CC, Seabra MC, Ericsson LH, Gelb MH, Glomset JA . Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A. Proc Natl Acad Sci USA 1994; 91: 11963–11967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Lebowitz PF, Prendergast GC . Non-Ras targets of farnesyltransferase inhibitors: focus on Rho. Oncogene 1998; 17: 1439–1445.

    Article  CAS  PubMed  Google Scholar 

  211. Farnsworth CC, Wolda SL, Gelb MH, Glomset JA . Human lamin B contains a farnesylated cysteine residue. J Biol Chem 1989; 264: 20422–20429.

    CAS  PubMed  Google Scholar 

  212. James GL, Goldstein JL, Pathak RK, Anderson RG, Brown MS . PxF, a prenylated protein of peroxisomes. J Biol Chem 1994; 269: 14182–14190.

    CAS  PubMed  Google Scholar 

  213. Lai RK, Perez-Sala D, Canada FJ, Rando RR . The gamma subunit of transducin is farnesylated. Proc Natl Acad Sci USA 1990; 87: 7673–7677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Inglese J, Glickman JF, Lorenz W, Caron MG, Lefkowitz RJ . Isoprenylation of a protein kinase Requirement of farnesylation/alpha-carboxyl methylation for full enzymatic activity of rhodopsin kinase. J Biol Chem 1992; 267: 1422–1425.

    CAS  PubMed  Google Scholar 

  215. Anant JS, Ong OC, Xie HY, Clarke S, O’Brien PJ, Fung BK . In vivo differential prenylation of retinal cyclic GMP phosphodiesterase catalytic subunits. J Biol Chem 1992; 267: 687–690.

    CAS  PubMed  Google Scholar 

  216. Heilmeyer Jr LM, Serwe M, Weber C, Metzger J, Hoffmann-Posorske E, Meyer HE . Farnesylcysteine, a constituent of the alpha and beta subunits of rabbit skeletal muscle phosphorylase kinase: localization by conversion to S-ethylcysteine and by tandem mass spectrometry. Proc Natl Acad Sci USA 1992; 89: 9554–9558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Kristine A Henningfeld for critically reading the manuscript. We apologize to those whose contributions have not been cited due to space constraints. This work was supported in part by a grant to CR from Hannover Medical School (HILF-program) a grant to CR from Deutsche Krebshilfe (10-1801-Re1) and a grant to MM from the International Myeloma Foundation.

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  1. Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M A Morgan, A Ganser & C W M Reuter

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  1. M A Morgan
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  2. A Ganser
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  3. C W M Reuter
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Morgan, M., Ganser, A. & Reuter, C. Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. Leukemia 17, 1482–1498 (2003). https://doi.org/10.1038/sj.leu.2403024

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  • DOI: https://doi.org/10.1038/sj.leu.2403024

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