Pediatrics, Division of Pediatric Hematology/Oncology
Laboratory Of Pediatric Hematologic Malignancies, David Sweetser (PI) http://www.massgeneral.org/cancer/research/basic/ccr/faculty/sweetser.asp
Key researchers: David Sweetser MD, PhD, Jianfeng Wang MD, PhD, Erica Tobey
Summary of Research
My lab seeks to identify novel tumor-suppressor genes involved in the pathogenesis of acute myeloid leukemia (AML) and to understand how inactivation of these genes cooperates with other genetic events in malignant transformation. AML is characterized by unique recurrent chromosomal translocations in over 50% of cases. However expression of the fusion genes created by these translocations are insufficient for leukemogenesis and in many cases only result in subtle changes in the bone marrow. Relatively little is known about how other mutations cooperate to cause leukemia. A major focus of the lab is to identify the critical gene(s) lost in AML samples with a deletion of a portion of the long arm of chromosome 9. About one half of these del(9q) AMLs cases are associated with the common translocation, t(8;21), which creates a chimeric transcription factor called RUNX1-MTG8/AML1-ETO. Since AML1-ETO alone is insufficient for leukemogenesis, these two lesions appear to cooperate in leukemogenesis. Using a combination of FISH and loss of heterozygosity (LOH) analyses in nearly 100 patients with AML and myelodysplastic syndrome, we have defined a commonly deleted segment on chromosome 9q of less than 2.4 Mb. This region corresponds to 9q21.32, has been completely sequenced, and harbors five known genes and six novel cDNAs. We have characterized the structure and expression of all these genes in normal bone marrow and various leukemias and have been testing these genes for effects on hematopoiesis and for tumor suppressor activity. Based on these analyses we have identified two genes from these region as novel candidate tumor suppressor genes in AML. Our work has demonstrated these genes can strongly influence both the proliferation and differentiation of myeloid cells and have tumor suppressor properties. Current work in our laboratory with conditional mouse models and cell culture systems are being used to further define the role of these genes in both normal hematopoiesis and leukemogenesis as well as the mechanism of cooperation between mutations in these genes and AML1-ETO or other gene mutations.
Contact Information
Phone: 617-724-5311
Fax: 617-726-8623
E-mail: dsweetser@partners.org
