Photo of David A. Sweetser,   M.D. Ph.D.

David A. Sweetser, M.D. Ph.D.

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-5311
Fax: (617) 726-1566

David A. Sweetser, M.D. Ph.D.

Massachusetts General Hospital


  • Assistant Professor, Pediatrics, Harvard Medical School
  • Pediatrician, Pediatric Hematology/Oncology, Massachusetts General Hospital
  • Chief of Medical Genetics and Metabolism, Pediatrics, Massachusetts General Hospital


Research Abstract

My laboratory interests span two major areas 1) Medical Genetics and Metabolism and 2) Leukemia. In Genetics my laboratory focuses on novel disease gene discovery in patients identified through the Undiagnosed Diseases Network, and investigating several genetic disorders including Pitt Hopkins Syndrome, IQSEC2-related disorder and CACNA1E epileptic encephalopathy. We have systematically and characterized patient derived induced pluripotent stem cell (iPSC) models of several inherited monogenic causes of intellectual disability and neurodevelopmental disorders developing phenotypic assays amenable to drug screening to precision targeted therapeutics.

In Leukemia we have identified two related genes, TLE1 and TLE4, as novel tumor suppressor genes that cooperate with other genetic events in malignant transformation. We have characterized the role of these proteins in leukemogenesis and normal hematopoiesis using a variety of in vivo and in vitro techniques. We have also characterized targetable intracellular signal pathways through which they exert their effects.

A second focus of the lab has been characterizing the components of the leukemic stem cell niche, especially miRNAs, and using this information to explore novel targeted therapies.

Publications from Harvard Catalyst Profiles

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  • Galazo MJ, Sweetser DA, Macklis JD. Tle4 controls both developmental acquisition and early post-natal maturation of corticothalamic projection neuron identity. Cell Rep 2023; 42:112957. PubMed
  • Morleo M, Venditti R, Theodorou E, Briere LC, Rosello M, Tirozzi A, Tammaro R, Al-Badri N, High FA, Shi J, , , Putti E, Ferrante L, Cetrangolo V, Torella A, Walker MA, Tenconi R, Iascone M, Mei D, Guerrini R, van der Smagt J, Kroes HY, van Gassen KLI, Bilal M, Umair M, Pingault V, Attie-Bitach T, Amiel J, Ejaz R, Rodan L, Zollino M, Agrawal PB, Del Bene F, Nigro V, Sweetser DA, Franco B. De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling. Am J Hum Genet 2023; 110:1377-1393. PubMed
  • Jangam S, Briere LC, Jay K, Andrews JC, Walker MA, Rodan LH, High FA, , Yamamoto S, Sweetser DA, Wangler M. A missense variant in associated with developmental delay exhibits functional deficits in . medRxiv 2023. PubMed
  • Lino Cardenas CL, Briere LC, Sweetser DA, Lindsay ME, Musolino PL. A seed sequence variant in miR-145-5p causes multisystem smooth muscle dysfunction syndrome. J Clin Invest 2023. PubMed
  • Huang Y, Lemire G, Briere LC, Liu F, Wessels MW, Wang X, Osmond M, Kanca O, Lu S, High FA, Walker MA, Rodan LH, , , Wangler MF, Yamamoto S, Kernohan KD, Sweetser DA, Boycott KM, Bellen HJ. The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability. Am J Hum Genet 2022; 109:2092. PubMed
  • Kozycki CT, Kodati S, Huryn L, Wang H, Warner BM, Jani P, Hammoud D, Abu-Asab MS, Jittayasothorn Y, Mattapallil MJ, Tsai WL, Ullah E, Zhou P, Tian X, Soldatos A, Moutsopoulos N, Kao-Hsieh M, Heller T, Cowen EW, Lee CR, Toro C, Kalsi S, Khavandgar Z, Baer A, Beach M, Long Priel D, Nehrebecky M, Rosenzweig S, Romeo T, Deuitch N, Brenchley L, Pelayo E, Zein W, Sen N, Yang AH, Farley G, Sweetser DA, Briere L, Yang J, de Oliveira Poswar F, Schwartz IVD, Silva Alves T, Dusser P, Koné-Paut I, Touitou I, Titah SM, van Hagen PM, van Wijck RTA, van der Spek PJ, Yano H, Benneche A, Apalset EM, Jansson RW, Caspi RR, Kuhns DB, Gadina M, Takada H, Ida H, Nishikomori R, Verrecchia E, Sangiorgi E, Manna R, Brooks BP, Sobrin L, Hufnagel RB, Beck D, Shao F, Ombrello AK, Aksentijevich I, Kastner DL, . Gain-of-function mutations in cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Ann Rheum Dis 2022. PubMed
  • Briere LC, Walker MA, High FA, Rogers CA, Callahan C, Cooper C, Ishimura R, Ichimura Y, Caruso PA, Sharma N, Brokamp E, Koziura ME, Mohammad SS, Dale RC, Riley LG, Network UD, Phillips JA, Komatsu M, Sweetser DA. A Description of Novel Variants and Review of Phenotypic Spectrum in UBA5-related Early Epileptic Encephalopathy. Cold Spring Harb Mol Case Stud 2021. PubMed
  • Shin TH, Theodorou E, Holland C, Yamin R, Raggio CL, Giampietro PF, Sweetser DA. TLE4 Is a Critical Mediator of Osteoblast and Runx2-Dependent Bone Development. Front Cell Dev Biol 2021; 9:671029. PubMed
  • Dutta D, Briere LC, Kanca O, Marcogliese PC, Walker MA, High FA, Vanderver A, Krier J, Carmichael N, Callahan C, Taft RJ, Simons C, Helman G, Network UD, Wangler MF, Yamamoto S, Sweetser DA, Bellen HJ. De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment. Hum Mol Genet 2020; 29:1568-1579. PubMed
  • Lee S, Micalizzi D, Truesdell SS, Bukhari SIA, Boukhali M, Lombardi-Story J, Kato Y, Choo MK, Dey-Guha I, Ji F, Nicholson BT, Myers DT, Lee D, Mazzola MA, Raheja R, Langenbucher A, Haradhvala NJ, Lawrence MS, Gandhi R, Tiedje C, Diaz-Muñoz MD, Sweetser DA, Sadreyev R, Sykes D, Haas W, Haber DA, Maheswaran S, Vasudevan S. A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells. Genome Biol 2020; 21:33. PubMed
  • Zollino M, Zweier C, Van Balkom ID, Sweetser DA, Alaimo J, Bijlsma EK, Cody J, Elsea SH, Giurgea I, Macchiaiolo M, Smigiel R, Thibert RL, Benoist I, Clayton-Smith J, De Winter CF, Deckers S, Gandhi A, Huisman S, Kempink D, Kruisinga F, Lamacchia V, Marangi G, Menke L, Mulder P, Nordgren A, Renieri A, Routledge S, Saunders CJ, Stembalska A, Van Balkom H, Whalen S, Hennekam RC. Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement. Clin Genet 2019; 95:462-478. PubMed
  • Xing S, Shao P, Li F, Zhao X, Seo W, Wheat JC, Ramasamy S, Wang J, Li X, Peng W, Yu S, Liu C, Taniuchi I, Sweetser DA, Xue HH. Tle corepressors are differentially partitioned to instruct CD8 T cell lineage choice and identity. J Exp Med 2018; 215:2211-2226. PubMed
  • Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, Gribouval O, Boyer O, Revy P, Jobst-Schwan T, Schmidt JM, Lawson JA, Schanze D, Ashraf S, Ullmann JFP, Hoogstraten CA, Boddaert N, Collinet B, Martin G, Liger D, Lovric S, Furlano M, Guerrera IC, Sanchez-Ferras O, Hu JF, Boschat AC, Sanquer S, Menten B, Vergult S, De Rocker N, Airik M, Hermle T, Shril S, Widmeier E, Gee HY, Choi WI, Sadowski CE, Pabst WL, Warejko JK, Daga A, Basta T, Matejas V, Scharmann K, Kienast SD, Behnam B, Beeson B, Begtrup A, Bruce M, Ch'ng GS, Lin SP, Chang JH, Chen CH, Cho MT, Gaffney PM, Gipson PE, Hsu CH, Kari JA, Ke YY, Kiraly-Borri C, Lai WM, Lemyre E, Littlejohn RO, Masri A, Moghtaderi M, Nakamura K, Ozaltin F, Praet M, Prasad C, Prytula A, Roeder ER, Rump P, Schnur RE, Shiihara T, Sinha MD, Soliman NA, Soulami K, Sweetser DA, Tsai WH, Tsai JD, Topaloglu R, Vester U, Viskochil DH, Vatanavicharn N, Waxler JL, Wierenga KJ, Wolf MTF, Wong SN, Leidel SA, Truglio G, Dedon PC, Poduri A, Mane S, Lifton RP, Bouchard M, Kannu P, Chitayat D, Magen D, Callewaert B, van Tilbeurgh H, Zenker M, Antignac C, Hildebrandt F. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet 2017; 49:1529-1538. PubMed
  • Lennerz JK, McLaughlin HM, Baron JM, Rasmussen D, Sumbada Shin M, Berners-Lee N, Miller Batten J, Swoboda KJ, Gala MK, Winter HS, Schmahmann JD, Sweetser DA, Boswell M, Pacula M, Stenzinger A, Le LP, Hynes W, Rehm HL, Klibanski A, Black-Schaffer SW, Golden JA, Louis DN, Weiss ST, Iafrate AJ. Health Care Infrastructure for Financially Sustainable Clinical Genomics. J Mol Diagn 2016; 18:697-706. PubMed
  • Shin TH, Brynczka C, Dayyani F, Rivera MN, Sweetser DA. TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia. Leuk Res 2016; 48:46-56. PubMed
  • Alexander-Bloch AF, McDougle CJ, Ullman Z, Sweetser DA. IQSEC2 and X-linked syndromal intellectual disability. 2016; 26:101-8. PubMed
  • Walker MA, Mohler KP, Hopkins KW, Oakley DH, Sweetser DA, Ibba M, Frosch MP, Thibert RL. Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease. J Child Neurol 2016. PubMed
  • Ramasamy S, Saez B, Mukhopadhyay S, Ding D, Ahmed AM, Chen X, Pucci F, Yamin R, Wang J, Pittet MJ, Kelleher CM, Scadden DT, Sweetser DA. Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway. Proc Natl Acad Sci U S A 2016; 113:1871-6. PubMed
  • Mason-Suares H, Sweetser DA, Lindeman NI, Morton CC. Training the Future Leaders in Personalized Medicine. J Pers Med 2016. PubMed
  • Consugar MB, Navarro-Gomez D, Place EM, Bujakowska KM, Sousa ME, Fonseca-Kelly ZD, Taub DG, Janessian M, Wang DY, Au ED, Sims KB, Sweetser DA, Fulton AB, Liu Q, Wiggs JL, Gai X, Pierce EA. Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing. Genet Med 2015; 17:253-61. PubMed
  • Wheat JC, Krause DS, Shin TH, Chen X, Wang J, Ding D, Yamin R, Sweetser DA. The corepressor Tle4 is a novel regulator of murine hematopoiesis and bone development. PLoS ONE 2014; 9:e105557. PubMed
  • Zhang Y, Wang J, Wheat J, Chen X, Jin S, Sadrzadeh H, Fathi AT, Peterson RT, Kung AL, Sweetser DA, Yeh JR. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway. Blood 2013; 121:4906-16. PubMed
  • Yeh JR,Munson KM,Elagib KE,Goldfarb AN,Sweetser DA,Peterson RT. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nat Chem Biol 2009; 5:236-43. PubMed
  • Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F, Sweetser DA, McClatchey AI, Bernard OA, Look AT, Bell DW, Scadden DT, Haber DA. Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 2008; 111:4716-22. PubMed
  • Dayyani F, Wang J, Yeh JR, Ahn EY, Tobey E, Zhang DE, Bernstein ID, Peterson RT, Sweetser DA. Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperate with AML1-ETO to affect myeloid cell proliferation and survival. Blood 2008; 111:4338-47. PubMed
  • Pollard JA, Alonzo TA, Gerbing RB, Woods WG, Lange BJ, Sweetser DA, Radich JP, Bernstein ID, Meshinchi S. FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia. Blood 2006; 108:2764-9. PubMed
  • Sweetser DA, Peniket AJ, Haaland C, Blomberg AA, Zhang Y, Zaidi ST, Dayyani F, Zhao Z, Heerema NA, Boultwood J, Dewald GW, Paietta E, Slovak ML, Willman CL, Wainscoat JS, Bernstein ID, Daly SB. Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 2005; 44:279-91. PubMed
  • Meshinchi S, Stirewalt DL, Alonzo TA, Zhang Q, Sweetser DA, Woods WG, Bernstein ID, Arceci RJ, Radich JP. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 2003; 102:1474-9. PubMed