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) 724-1911

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 lab seeks to identify novel tumor suppressor genes involved in the pathogenesis of acute myeloid leukemia (AML) in order to understand how inactivation of these genes cooperates with other genetic events in malignant transformation. A major focus of the lab has been to identify the critical gene(s) lost in AML samples with a deletion of a portion of the long arm of chromosome 9. In about one third to one half of these cases, del(9q) is associated with the common translocation, t(8;21), which creates a chimeric transcription factor called AML1-ETO1. Since AML1-ETO1 alone is apparently insufficient for leukemogenesis, it is likely these two lesions cooperate in leukemogenesis. Using a combination of FISH and loss of heterozygosity (LOH) analyses, we have defined a commonly deleted segment on chromosome 9q of less than 2.1 Mb at 9q21.32. We used a novel in vitro complementation assay to identify two related genes, TLE1 and TLE4, as the most likely candidate tumor suppressor genes from this region. We are now characterizing the role of these proteins in leukemogenesis and normal hematopoiesis using a variety of in vivo and in vitro techniques. We are also characterizing the intracellular signal pathways through which they exert their effects.

We believe that identification and characterization of these genes and other cooperating transforming genes may yield new potential targets for therapy as well as delineate subgroups of patients with differing prognostic features. Identification of cooperating genetic mutations may also allow a more accurate assessment of minimal residual disease in AML during and after treatment and may help identify individuals at high risk of relapse.

Publications from Harvard Catalyst Profiles

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  • 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
  • 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
  • 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
  • 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
  • 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