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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  • 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
  • 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
  • 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
  • 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
  • Murase K, Kim HT, Bascug OR, Kawano Y, Ryan J, Matsuoka KI, 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
  • 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 Flourimeter 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
  • Kutuk O, Letai A. Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol Med 2008; 8:102-18. 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
  • 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
  • Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005; 8:407-19. PubMed
  • Letai A. Pharmacological manipulation of Bcl-2 family members to control cell death. J Clin Invest 2005; 115:2648-55. PubMed
  • Letai A. BCL-2: found bound and drugged! Trends Mol Med 2005; 11:442-4. PubMed
  • Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435:677-81. PubMed
  • Letai A, Sorcinelli MD, Beard C, Korsmeyer SJ. Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell 2004; 6:241-9. PubMed
  • Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003; 426:671-6. PubMed
  • Letai A. BH3 domains as BCL-2 inhibitors: prototype cancer therapeutics. Expert Opin Biol Ther 2003; 3:293-304. PubMed
  • Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2:183-92. PubMed
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