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) 726-8623

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

Massachusetts General Hospital


  • Assistant Professor, Pediatrics, Harvard Medical School
  • Associate Pediatrician, Pediatric Hematology/Oncology, 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.


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  • 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/็กซ-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
  • Sweetser DA, Chen CS, Blomberg AA, Flowers DA, Galipeau PC, Barrett MT, Heerema NA, Buckley J, Woods WG, Bernstein ID, Reid BJ. Loss of heterozygosity in childhood de novo acute myelogenous leukemia. Blood 2001; 98:1188-94. PubMed
  • Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, Bernstein ID, Radich JP. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001; 97:89-94. PubMed
  • Rice J, Doggett B, Sweetser DA, Yanagisawa H, Yanagisawa M, Kapur RP. Transgenic rescue of aganglionosis and piebaldism in lethal spotted mice. Dev Dyn 2000; 217:120-32. PubMed
  • Gestblom C, Sweetser DA, Doggett B, Kapur RP. Sympathoadrenal hyperplasia causes renal malformations in Ret(MEN2B)-transgenic mice. Am J Pathol 1999; 155:2167-79. PubMed
  • Sweetser DA, Froelick GJ, Matsumoto AM, Kafer KE, Marck B, Palmiter RD, Kapur RP. Ganglioneuromas and renal anomalies are induced by activated RET(MEN2B) in transgenic mice. Oncogene 1999; 18:877-86. PubMed
  • Sweetser DA, Kapur RP, Froelick GJ, Kafer KE, Palmiter RD. Oncogenesis and altered differentiation induced by activated Ras in neuroblasts of transgenic mice. Oncogene 1998; 15:2783-94. PubMed
  • Kapur RP, Livingston R, Doggett B, Sweetser DA, Siebert JR, Palmiter RD. Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice. Dev Biol 1996; 174:360-9. PubMed
  • Steiner RD, Sweetser DA, Rohrbaugh JR, Dowton SB, Toone JR, Applegarth DA. Nonketotic hyperglycinemia: atypical clinical and biochemical manifestations. J Pediatr 1996; 128:243-6. PubMed
  • Kapur RP, Sweetser DA, Doggett B, Siebert JR, Palmiter RD. Intercellular signals downstream of endothelin receptor-B mediate colonization of the large intestine by enteric neuroblasts. Development 1995; 121:3787-95. PubMed
  • Edelhoff S, Sweetser DA, Disteche CM. Mapping of the NEP receptor tyrosine kinase gene to human chromosome 6p21.3 and mouse chromosome 17C. Genomics 1995; 25:309-11. PubMed
  • Herman TE, Sweetser DA, McAlister WH, Dowton SB. Schinzel-Giedion syndrome and congenital megacalyces. Pediatr Radiol 1993; 23:111-2. PubMed
  • Hauft SM, Sweetser DA, Rotwein PS, Lajara R, Hoppe PC, Birkenmeier EH, Gordon JI. A transgenic mouse model that is useful for analyzing cellular and geographic differentiation of the intestine during fetal development. J Biol Chem 1989; 264:8419-29. PubMed
  • Sweetser DA, Hauft SM, Hoppe PC, Birkenmeier EH, Gordon JI. Transgenic mice containing intestinal fatty acid-binding protein-human growth hormone fusion genes exhibit correct regional and cell-specific expression of the reporter gene in their small intestine. Proc Natl Acad Sci U S A 1988; 85:9611-5. PubMed
  • Sweetser DA, Birkenmeier EH, Hoppe PC, McKeel DW, Gordon JI. Mechanisms underlying generation of gradients in gene expression within the intestine: an analysis using transgenic mice containing fatty acid binding protein-human growth hormone fusion genes. Genes Dev 1988; 2:1318-32. PubMed
  • Sweetser DA, Birkenmeier EH, Klisak IJ, Zollman S, Sparkes RS, Mohandas T, Lusis AJ, Gordon JI. The human and rodent intestinal fatty acid binding protein genes. A comparative analysis of their structure, expression, and linkage relationships. J Biol Chem 1987; 262:16060-71. PubMed
  • Demmer LA, Birkenmeier EH, Sweetser DA, Levin MS, Zollman S, Sparkes RS, Mohandas T, Lusis AJ, Gordon JI. The cellular retinol binding protein II gene. Sequence analysis of the rat gene, chromosomal localization in mice and humans, and documentation of its close linkage to the cellular retinol binding protein gene. J Biol Chem 1987; 262:2458-67. PubMed
  • Sweetser DA, Heuckeroth RO, Gordon JI. The metabolic significance of mammalian fatty-acid-binding proteins: abundant proteins in search of a function. Annu Rev Nutr 1986; 7:337-59. PubMed
  • Li E, Demmer LA, Sweetser DA, Ong DE, Gordon JI. Rat cellular retinol-binding protein II: use of a cloned cDNA to define its primary structure, tissue-specific expression, and developmental regulation. Proc Natl Acad Sci U S A 1986; 83:5779-83. PubMed
  • Sweetser DA, Lowe JB, Gordon JI. The nucleotide sequence of the rat liver fatty acid-binding protein gene. Evidence that exon 1 encodes an oligopeptide domain shared by a family of proteins which bind hydrophobic ligands. J Biol Chem 1986; 261:5553-61. PubMed
  • Lowe JB, Boguski MS, Sweetser DA, Elshourbagy NA, Taylor JM, Gordon JI. Human liver fatty acid binding protein. Isolation of a full length cDNA and comparative sequence analyses of orthologous and paralogous proteins. J Biol Chem 1985; 260:3413-7. PubMed