The DAC system and associations with acute leukemias and myelodysplastic syndromes

Investigational New Drugs - Tập 28 - Trang 36-49 - 2010
Gesine Bug1, Oliver G. Ottmann1
1Medizinische Klinik II, Abteilung für Hämatologie und Onkologie der, Goethe-Universität, Frankfurt, Germany

Tóm tắt

Imbalances of histone acetyltransferase (HAT) and deacetylase activity (DAC) that result in deregulated gene expression are commonly observed in leukemias. These alterations provide the basis for novel therapeutic approaches that target the epigenetic mechanisms implicated in leukemogenesis. As the acetylation status of histones has been linked to transcriptional regulation of genes involved particularly in differentiation and apoptosis, DAC inhibitors (DACi) have attracted considerable attention for treatment of hematologic malignancies. DACi encompass a structurally diverse family of compounds that are being explored as single agents as well as in combination with chemotherapeutic drugs, small molecule inhibitors of signaling pathways and hypomethylating agents. While DACi have shown clear evidence of activity in acute myeloid leukemia, myelodysplastic syndromes and lymphoid malignancies, their precise role in treatment of these different entities remain to be elucidated. Successful development of these compounds as elements of novel targeted treatment strategies for leukemia will require that clinical studies be performed in conjunction with translational research including efforts to identify predictive biomarkers.

Tài liệu tham khảo

Weichert W (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Lett 280(2):168–176 Redner R, Wang J, Liu J (1999) Chromatin remodelling and leukemia: new therapeutic paradigms. Blood 94:417–428 Jones LK, Saha V (2002) Chromatin modification, leukaemia and implications for therapy. Br J Haematol 118(3):714–727 Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1(3):194–202 Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4(1):13–18 Lindemann RK, Gabrielli B, Johnstone RW (2004) Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle 3(6):779–788 Scandura JM, Boccuni P, Cammenga J, Nimer SD (2002) Transcription factor fusions in acute leukemia: variations on a theme. Oncogene 21(21):3422–3444 Durst KL, Hiebert SW (2004) Role of RUNX family members in transcriptional repression and gene silencing. Oncogene 23(24):4220–4224 So CW, Cleary ML (2004) Dimerization: a versatile switch for oncogenesis. Blood 104(4):919–922 Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS et al (1996) The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 14(1):33–41 Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B et al (1997) MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci USA 94(16):8732–8737 Linggi B, Muller-Tidow C, van de Locht L, Hu M, Nip J, Serve H et al (2002) The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nat Med 8(7):743–750 Krug U, Ganser A, Koeffler HP (2002) Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene 21(21):3475–3495 Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL et al (2005) Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res 65(4):1277–1284 Yang XJ, Ullah M (2007) MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells. Oncogene 26(37):5408–5419 Rebel VI, Kung AL, Tanner EA, Yang H, Bronson RT, Livingston DM (2002) Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci USA 99(23):14789–14794 Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF et al (2000) Mutations truncating the EP300 acetylase in human cancers. Nat Genet 24(3):300–303 Yang XJ (2004) The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 32(3):959–976 Blobel GA (2000) CREB-binding protein and p300: molecular integrators of hematopoietic transcription. Blood 95(3):745–755 Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S et al (1997) All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90(2):535–541 Pui CH, Relling MV, Downing JR (2004) Acute lymphoblastic leukemia. N Engl J Med 350(15):1535–1548 Zelent A, Greaves M, Enver T (2004) Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 23(24):4275–4283 Agirre X, Vilas-Zornoza A, Jimenez-Velasco A, Martin-Subero JI, Cordeu L, Garate L et al (2009) Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Res 69(10):4443–4453 Marchion D, Munster P (2007) Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther 7(4):583–598 Dokmanovic M, Marks PA (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96(2):293–304 Gray SG, Qian CN, Furge K, Guo X, Teh BT (2004) Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol 24(4):773–795 Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA et al (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 102(10):3697–3702 Bhalla KN (2005) Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol 23(17):3971–3993 Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA 100(8):4389–4394 Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T (2002) Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem 277(28):25562–25567 Bannister AJ, Miska EA, Gorlich D, Kouzarides T (2000) Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr Biol 10(8):467–470 Blander G, Zalle N, Daniely Y, Taplick J, Gray MD, Oren M (2002) DNA damage-induced translocation of the Werner helicase is regulated by acetylation. J Biol Chem 277(52):50934–50940 Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C et al (2004) Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13(5):627–638 Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H et al (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2(10):971–984 Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A et al (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–458 Polevoda B, Sherman F (2002) The diversity of acetylated proteins. Genome Biol 3(5):reviews0006 Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51 Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23 Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A et al (2005) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nature Med 11(1):71–76 Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med 11(1):77–84 Reikvam H, Ersvaer E, Bruserud O (2009) Heat shock protein 90—a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 9(6):761–776 Göttlicher M, Minucci S, Zhu J, Krämer O, Schimpf A, Giavara S et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978 Liu S, Klisovic RB, Vukosavljevic T, Yu J, Paschka P, Huynh L et al (2007) Targeting AML1/ETO-histone deacetylase repressor complex: a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells. J Pharmacol Exp Ther 321(3):953–960 Bug G, Schwarz K, Schoch C, Kampfmann M, Henschler R, Hoelzer D et al (2007) Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia. Haematologica 92(4):542–545 Barbetti V, Gozzini A, Rovida E, Morandi A, Spinelli E, Fossati G et al (2008) Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells. Oncogene 27(12):1767–1778 Murata M, Towatari M, Kosugi H, Tanimoto M, Ueda R, Saito H et al (2000) Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells. Jpn J Cancer Res 91(11):1154–1160 Romanski A, Bacic B, Bug G, Pfeifer H, Gul H, Remiszewski S et al (2004) Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia. Haematologica 89(4):419–426 Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P et al (2008) The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph-acute lymphoblastic leukemia cells. Blood 111(10):5093–5100 Tsapis M, Lieb M, Manzo F, Shankaranarayanan P, Herbrecht R, Lutz P et al (2007) HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway. Int J Biochem Cell Biol 39(7–8):1500–1509 Stams WA, den Boer ML, Beverloo HB, Kazemier KM, van Wering ER, Janka-Schaub GE et al (2005) Effect of the histone deacetylase inhibitor depsipeptide on B-cell differentiation in both TEL-AML1-positive and negative childhood acute lymphoblastic leukemia. Haematologica 90(12):1697–1699 Einsiedel HG, Kawan L, Eckert C, Witt O, Fichtner I, Henze G et al (2006) Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia. Leukemia 20(8):1435–1436 Richon VM, Webb Y, Merger R, Sheppard T, Jursic B, Ngo L et al (1996) Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc Natl Acad Sci USA 93(12):5705–5708 Archer SY, Meng S, Shei A, Hodin RA (1998) p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci USA 95(12):6791–6796 He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, Rifkind RA et al (2001) Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Investig 108(9):1321–1330 Ferrara F, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S et al (2001) Histone deacytylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2–7 Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21(1):103–107 Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat reviews 5(9):769–784 Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini JL et al (2008) A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts. Cell Cycle 7(14):2139–2145 Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R et al (2009) Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 8(10):939–950 Huang Y, Waxman S (1998) Enhanced growth inhibition and differentiation of fluorodeoxyuridine-treated human colon carcinoma cells by phenylbutyrate. Clin Cancer Res 4(10):2503–2509 Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300 Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T et al (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 101(2):540–545 Witzig TE, Timm M, Stenson M, Svingen PA, Kaufmann SH (2000) Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin Cancer Res 6(2):681–692 Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN (2004) Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92(2):223–237 Kurz EU, Wilson SE, Leader KB, Sampey BP, Allan WP, Yalowich JC et al (2001) The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines. Mol Cancer Ther 1(2):121–131 Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM et al (2006) Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood 108(4):1174–1182 Maiso P, Colado E, Ocio EM, Garayoa M, Martin J, Atadja P et al (2009) The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 23(12):2265–2274 Shiozawa K, Nakanishi T, Tan M, Fang HB, Wang WC, Edelman MJ et al (2009) Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Clin Cancer Res 15(5):1698–1707 Maggio SC, Rosato RR, Kramer LB, Dai Y, Rahmani M, Paik DS et al (2004) The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res 64(7):2590–2600 Leclerc GJ, Mou C, Leclerc GM, Mian AM, Barredo JC (2010) Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia 24(3):552–562 Bali P, George P, Cohen P, Tao J, Guo F, Sigua C et al (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10(15):4991–4997 Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A (2008) Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia 22(12):2159–2168 Kircher B, Schumacher P, Petzer A, Hoflehner E, Haun M, Wolf AM et al (2009) Anti-leukemic activity of valproic acid and imatinib mesylate on human Ph + ALL and CML cells in vitro. Eur J Haematol 83(1):48–56 Miller CP, Ban K, Dujka ME, McConkey DJ, Munsell M, Palladino M et al (2007) NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110(1):267–277 Miller CP, Rudra S, Keating MJ, Wierda WG, Palladino M, Chandra J (2009) Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells. Blood 113(18):4289–4299 Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, et al (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. May 20 Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C et al (2005) Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 84(Suppl 13):61–66 Kuendgen A, Gattermann N (2007) Valproic acid for the treatment of myeloid malignancies. Cancer 110(5):943–954 Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C et al (2006) The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106(1):112–119 Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K et al (2005) Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 104(12):2717–2725 Cimino G, Lo-Coco F, Fenu S, Travaglini L, Finolezzi E, Mancini M et al (2006) Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. Cancer Res 66(17):8903–8911 Raffoux E, Chaibi P, Dombret H, Degos L (2005) Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 90(7):986–988 Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG et al (2008) Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111(3):1060–1066 Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J et al (2009) A phase 2 study of vorinostat in acute myeloid leukemia. Haematologica 94(10):1375–1382 Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F et al (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12(15):4628–4635 Ottmann O, Spencer A, Prince H, Bhalla K, Fischer T, Liu A et al (2008) Phase IA/II study of oral panobinostat (LBH589), a novel pan-deacetylase inhibitor (DACi) demonstrating efficacy in patients with advanced hematologic malignancies. Blood 112:a958 Odenike OM, Alkan S, Sher D, Godwin JE, Huo D, Brandt SJ et al (2008) Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia. Clin Cancer Res 14(21):7095–7101 Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N et al (2008) Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res 14(3):826–832 Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE et al (2008) A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 81(3):170–176 Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H et al (2008) Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112(4):981–989 Gojo I, Jiemjit A, Trepel JB, Sparreboom A, Figg WD, Rollins S et al (2007) Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109(7):2781–2790 Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR et al (2006) Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 12(12):3762–3773 Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, et al (2006) Phase I/II study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. Aug 1 Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H et al (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25(25):3884–3891 Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F et al (2007) Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110(7):2302–2308 Voso MT, Santini V, Finelli C, Musto P, Pogliani E, Angelucci E et al (2009) Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 15(15):5002–5007 Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M et al (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66(12):6361–6369 Kirschbaum M, Gojo I, Goldberg S, Kujawski L, Atallah E, Marks PA et al (2009) Vorinostat in combination with decitabine for the treatment of relapsed or newly diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS): a phase i, dose-escalation study. Blood 114:2089a Kadia T, Estrov Z, Ravandi F, Koller C, Borthakur G, Jabbour E et al (2009) Long term followup and patterns of failure in patients with Acute Myeloid Leukemia (AML) and high risk Myelodysplastic Syndrome (MDS) treated on studies combining a hypomethylating agent and the histone deacetylase inhibitor (HDACi) valproic acid. Blood 114:2074a Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, et al (2010) A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Br J Haematol. Apr 29 Garcia-Manero G, Tambaro F, Bekele B, Jabbour E, Ravandi F, Yang H et al (2009) Phase II study of vorinostat in combination with idarubicin (Ida) and cytarabine (ara-C) as front line therapy in Acute Myelogenous Leukemia (AML) or higher risk myelodysplastic syndrome (MDS). Blood 114:1055a Hauswald S, Duque-Afonso J, Wagner MM, Schertl FM, Lubbert M, Peschel C et al (2009) Histone deacetylase inhibitors induce a very broad, pleiotropic anticancer drug resistance phenotype in acute myeloid leukemia cells by modulation of multiple ABC transporter genes. Clin Cancer Res 15(11):3705–3715 Tabe Y, Konopleva M, Contractor R, Munsell M, Schober WD, Jin L et al (2006) Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood 107(4):1546–1554