Photo of Anthony G. Letai,  MD, PHD

Anthony G. Letai, MD, PHD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-2348
Fax: (617) 582-8160


anthony_letai@dfci.harvard.edu

Anthony G. Letai, MD, PHD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Professor of Medicine, Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory investigates the role of apoptotic dysfunction in tumor maintenance. Members of the BCL-2 family of proteins are critical adjudicators of death decisions. We are studying how interactions among anti-apoptotic members (including BCL-2, BCL-XL, MCL-1, BFL-1/A1, and BCL-w) and BH3-only pro-apoptotic members (including BID, BAD, BIM, BIK, PUMA, NOXA, BMF, and Hari-Kiri) can determine cancer cell survival. We are also investigating mimetics of BH3 domains derived from these proteins (including peptides and small molecules) as inhibitors of BCL-2 and the other anti-apoptotic proteins. We utilize a conditional transgenic mouse model of a BCL-2 dependent leukemia. We also study the mechanisms of mitochondrial dysfunction associated with apoptosis in normal and cancer cells. Our goal is to define the dependence of cancer cells on apoptotic dysfunction, and to target this dysfunction to specifically kill cancer cell.

Publications

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  • Brem EA, Letai A. BOK: Oddball of the BCL-2 Family. Trends Cell Biol 2016; 26:389-90. PubMed
  • Montero J, Letai A. Dynamic BH3 profiling-poking cancer cells with a stick. Mol Cell Oncol 2016; 3:e1040144. PubMed
  • Pallis M, Burrows F, Ryan J, Grundy M, Seedhouse C, Abdul-Aziz A, Montero J, Letai A, Russell N. Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. 2016. PubMed
  • Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG, Majewski IJ, Segal D, Heitner Enschede SL, Huang DC, Davids MS, Letai A, Roberts AW. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism. Blood 2016. PubMed
  • Townsend EC, Murakami MA, Christodoulou A, Christie AL, Köster J, DeSouza TA, Morgan EA, Kallgren SP, Liu H, Wu SC, Plana O, Montero J, Stevenson KE, Rao P, Vadhi R, Andreeff M, Armand P, Ballen KK, Barzaghi-Rinaudo P, Cahill S, Clark RA, Cooke VG, Davids MS, DeAngelo DJ, Dorfman DM, Eaton H, Ebert BL, Etchin J, Firestone B, Fisher DC, Freedman AS, Galinsky IA, Gao H, Garcia JS, Garnache-Ottou F, Graubert TA, Gutierrez A, Halilovic E, Harris MH, Herbert ZT, Horwitz SM, Inghirami G, Intlekoffer AM, Ito M, Izraeli S, Jacobsen ED, Jacobson CA, Jeay S, Jeremias I, Kelliher MA, Koch R, Konopleva M, Kopp N, Kornblau SM, Kung AL, Kupper TS, LaBoeuf N, LaCasce AS, Lees E, Li LS, Look AT, Murakami M, Muschen M, Neuberg D, Ng SY, Odejide OO, Orkin SH, Paquette RR, Place AE, Roderick JE, Ryan JA, Sallan SE, Shoji B, Silverman LB, Soiffer RJ, Steensma DP, Stegmaier K, Stone RM, Tamburini J, Thorner AR, van Hummelen P, Wadleigh M, Wiesmann M, Weng AP, Wuerthner JU, Williams DA, Wollison BM, Lane AA, Letai A, Bertagnolli MM, Ritz J, Brown M, Long H, Aster JC, Shipp MA, Griffin JD, Weinstock DM. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 2016; 29:574-86. PubMed
  • Sarosiek KA, Letai A. Directly targeting the mitochondrial pathway of apoptosis for cancer therapy with BH3 mimetics: recent successes, current challenges and future promise. FEBS J 2016. PubMed
  • Koss B, Ryan J, Budhraja A, Szarama K, Yang X, Bathina M, Cardone MH, Nikolovska-Coleska Z, Letai A, Opferman JT. Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines. 2016; 7:11500-11. PubMed
  • Ryan J, Montero J, Rocco J, Letai A. iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry. Biol Chem 2016. PubMed
  • Rezaei Araghi R, Ryan JA, Letai A, Keating AE. Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains. ACS Chem Biol 2016. PubMed
  • Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K, Wang L, Stewart C, Fan J, Hoellenriegel J, Sivina M, Dubuc AM, Fraser C, Han Y, Li S, Livak KJ, Zou L, Wan Y, Konoplev S, Sougnez C, Brown JR, Abruzzo LV, Carter SL, Keating MJ, Davids MS, Wierda WG, Cibulskis K, Zenz T, Werner L, Dal Cin P, Kharchencko P, Neuberg D, Kantarjian H, Lander E, Gabriel S, O'Brien S, Letai A, Weitz DA, Nowak MA, Getz G, Wu CJ. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun 2016; 7:11589. PubMed
  • Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, Marzo I, Harutyunyan KG, Golfman L, North P, Kerry J, Ballabio E, Chonghaile TN, Gonzalo O, Qiu Y, Jeremias I, Debose L, O'Brien E, Ma H, Zhou P, Jacamo R, Park E, Coombes KR, Zhang N, Thomas DA, O'Brien S, Kantarjian HM, Leverson JD, Kornblau SM, Andreeff M, Müschen M, Zweidler-McKay PA, Mulloy JC, Letai A, Milne TA, Konopleva M. MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199. Cell Rep 2016; 13:2715-27. PubMed
  • Friedman AA, Letai A, Fisher DE, Flaherty KT. Precision medicine for cancer with next-generation functional diagnostics. Nat Rev Cancer 2015; 15:747-56. PubMed
  • Letai A. Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell! Clin Cancer Res 2015; 21:5015-20. PubMed
  • Bhatt S, Matthews J, Parvin S, Sarosiek KA, Zhao D, Jiang X, Isik E, Letai A, Lossos IS. Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma. Blood 2015; 126:1555-64. PubMed
  • Etchin J, Montero J, Berezovskaya A, Le BT, Kentsis A, Christie AL, Conway AS, Chen WC, Reed C, Mansour MR, Ng CE, Adamia S, Rodig SJ, Galinsky IA, Stone RM, Klebanov B, Landesman Y, Kauffman M, Shacham S, Kung AL, Wang JC, Letai A, Look AT. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice. Leukemia 2015. PubMed
  • Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, Christie AL, Liu H, Christodoulou A, van Bodegom D, van der Zwet J, Layer JV, Tivey T, Lane AA, Ryan JA, Ng SY, DeAngelo DJ, Stone RM, Steensma D, Wadleigh M, Harris M, Mandon E, Ebel N, Andraos R, Romanet V, Dölemeyer A, Sterker D, Zender M, Rodig SJ, Murakami M, Hofmann F, Kuo F, Eck MJ, Silverman LB, Sallan SE, Letai A, Baffert F, Vangrevelinghe E, Radimerski T, Gaul C, Weinstock DM. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell 2015; 28:29-41. PubMed
  • Dutta S, Ryan J, Chen TS, Kougentakis C, Letai A, Keating AE. Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL. J Mol Biol 2015; 427:1241-53. PubMed
  • Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, Piao H, Horowitz NS, Berkowitz RS, Matulonis U, Jänne PA, Amrein PC, Cichowski K, Drapkin R, Letai A. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 2015; 160:977-89. PubMed
  • Winter PS, Sarosiek KA, Lin KH, Meggendorfer M, Schnittger S, Letai A, Wood KC. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal 2014; 7:ra122. PubMed
  • Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE. Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol 2014; 9:1962-8. PubMed
  • Chonghaile TN, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB, Loh ML, Hunger SP, Wood B, DeAngelo DJ, Stone R, Harris M, Gutierrez A, Kelliher MA, Letai A. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. 2014; 4:1074-87. PubMed
  • Suryani S, Carol H, Chonghaile TN, Frismantas V, Sarmah C, High L, Bornhauser B, Cowley MJ, Szymanska B, Evans K, Boehm I, Tonna E, Jones L, Manesh DM, Kurmasheva RT, Billups C, Kaplan W, Letai A, Bourquin JP, Houghton PJ, Smith MA, Lock RB. Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. Clin Cancer Res 2014; 20:4520-31. PubMed
  • Murase K, Kim HT, Bascug OR, Kawano Y, Ryan J, Matsuoka K, Davids MS, Koreth J, Ho VT, Cutler C, Armand P, Alyea EP, Blazar BR, Antin JH, Soiffer RJ, Letai A, Ritz J. Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation. Haematologica 2014. PubMed
  • Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA, Walton Z, Sarosiek KA, Letai A, Heist RS, Mino-Kenudson M, Wong KK, Engelman JA. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Res 2014. PubMed
  • Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, Cortes J, DeAngelo DJ, Debose L, Mu H, Döhner H, Gaidzik VI, Galinsky I, Golfman LS, Haferlach T, Harutyunyan KG, Hu J, Leverson JD, Marcucci G, Müschen M, Newman R, Park E, Ruvolo PP, Ruvolo V, Ryan J, Schindela S, Zweidler-McKay P, Stone RM, Kantarjian H, Andreeff M, Konopleva M, Letai AG. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. 2014; 4:362-75. PubMed
  • Liu JC, Guan X, Ryan JA, Rivera AG, Mock C, Agrawal V, Agarwal V, Letai A, Lerou PH, Lahav G. High mitochondrial priming sensitizes hESCs to DNA-damage-induced apoptosis. Cell Stem Cell 2013; 13:483-91. PubMed
  • Davids MS, Letai A, Brown JR. Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition. Leuk Lymphoma 2013. PubMed
  • Ryan J, Letai A. BH3 profiling in whole cells by fluorimeter or FACS. Methods 2013. PubMed
  • Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, Christie AL, McCauley D, Rodig SJ, Kauffman M, Shacham S, Stone R, Letai A, Kung AL, Thomas Look A. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. British Journal of Haematology 2013; 161:117-27. PubMed
  • Hogdal LJ, Letai A. BCL-2 inhibition: stemming the tide of myeloid malignancies. Cell Stem Cell 2013; 12:269-70. PubMed
  • Davids MS, Letai A. ABT-199: taking dead aim at BCL-2. Cancer Cell 2013; 23:139-41. PubMed
  • Davids MS, Deng J, Wiestner A, Lannutti BJ, Wang L, Wu CJ, Wilson WH, Brown JR, Letai A. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 2012; 120:3501-9. PubMed
  • Vo TT, Ryan J, Carrasco R, Neuberg D, Rossi DJ, Stone RM, Deangelo DJ, Frattini MG, Letai A. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 2012; 151:344-55. PubMed
  • Ercan D, Xu C, Yanagita M, Monast CS, Pratilas CA, Montero J, Butaney M, Shimamura T, Sholl L, Ivanova EV, Tadi M, Rogers A, Repellin C, Capelletti M, Maertens O, Goetz EM, Letai A, Garraway LA, Lazzara MJ, Rosen N, Gray NS, Wong KK, Jänne PA. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. 2012; 2:934-47. PubMed
  • Dutta C, Day T, Kopp N, van Bodegom D, Davids MS, Ryan J, Bird L, Kommajosyula N, Weigert O, Yoda A, Fung H, Brown JR, Shapiro GI, Letai A, Weinstock DM. BCL2 suppresses PARP1 function and nonapoptotic cell death. Cancer Res 2012; 72:4193-203. PubMed
  • Letai A. A new face of BCL-2 inhibition in CLL. Blood 2011; 117:2750-1. PubMed
  • Ryan JA, Brunelle JK, Letai A. Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci U S A 2010; 107:12895-900. PubMed
  • Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010; 115:3304-13. PubMed
  • Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463:899-905. PubMed
  • Vo TT, Letai A. BH3-only proteins and their effects on cancer. Adv Exp Med Biol 2010; 687:49-63. PubMed
  • Brunelle JK, Ryan J, Yecies D, Opferman JT, Letai A. MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts. J Cell Biol 2009; 187:429-42. PubMed
  • Dutta-Simmons J, Zhang Y, Gorgun G, Gatt M, Mani M, Hideshima T, Takada K, Carlson NE, Carrasco DE, Tai YT, Raje N, Letai AG, Anderson KC, Carrasco DR. Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood 2009; 114:2699-708. PubMed
  • Letai A. Hiding from ABT-737 in lymph nodes. Blood 2009; 113:4132-3. PubMed
  • Letai A. Puma strikes Bax. J Cell Biol 2009; 185:189-91. PubMed
  • Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 2009; 122:437-41. PubMed
  • Jette CA, Flanagan AM, Ryan J, Pyati UJ, Carbonneau S, Stewart RA, Langenau DM, Look AT, Letai A. BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals. Cell Death Differ 2008; 15:1063-72. PubMed
  • Flanagan AM, Letai A. BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2. Cell Death Differ 2007; 15:580-8. PubMed
  • Kutuk O, Letai A. Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol Med 2008; 8:102-18. PubMed
  • Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 2007; 111:2300-9. PubMed
  • Letai AG. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer 2008; 8:121-32. PubMed
  • Del Gaizo Moore V, Letai A. Rational design of therapeutics targeting the BCL-2 family: are some cancer cells primed for death but waiting for a final push? Adv Exp Med Biol 2008; 615:159-75. PubMed
  • Deng J, Shimamura T, Perera S, Carlson NE, Cai D, Shapiro GI, Wong KK, Letai A. Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res 2007; 67:11867-75. PubMed
  • Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007; 12:171-85. PubMed
  • Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007; 117:112-21. PubMed
  • Letai A. Restoring cancer's death sentence. Cancer Cell 2006; 10:343-5. PubMed
  • Goldsmith KC, Liu X, Dam V, Morgan BT, Shabbout M, Cnaan A, Letai A, Korsmeyer SJ, Hogarty MD. BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma. Oncogene 2006; 25:4525-33. PubMed
  • Letai A, Scorrano L. Laying the foundations of programmed cell death. Cell Death Differ 2006; 13:1245-7. PubMed
  • Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9:351-65. PubMed
  • Letai A. Growth factor withdrawal and apoptosis: the middle game. Mol Cell 2006; 21:728-30. PubMed
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