Researcher Profile
Margaret A. Shipp, MD
Professor of Medicine, Harvard Medical School
Center/Program
Department
Medical Oncology/Hematologic Neoplasia
Interest
Lymphoma
Area of Research
Diffuse Large B Cell Lymphoma
Contact Information
Margaret A. Shipp, MDDana-Farber Cancer Institute
44 Binney Street
Mayer 513
Boston, MA 02115
Office phone: (617) 632-3874
Fax: (617) 632-4734
Preferred contact method: office phone
Research
The efforts of our clinical, translational, and basic laboratory group are focused on aggressive B cell lymphomas, with specific emphasis on the most common lymphoid malignancy, diffuse large B cell lymphoma (DLBCL). Previously, our clinical group developed a broadly applicable clinical prognostic factor model, the International Prognostic Index, that identifies patients with aggressive lymphomas who have different likelihoods of being cured with best standard therapy. Our laboratory group has attempted to identify cellular and molecular bases for the observed clinical heterogeneity in DLBCL and use this information to credential more rational therapeutic targets. Our group has developed genomewide approaches to define the unique molecular signatures (transcriptional profiles) of specific DLBCL subtypes and more rational therapeutic targets. Our pilot studies identified several signaling pathways associated with resistance to standard therapy, and two of these pathways have now been credentialed as rational therapeutic targets in DLBCL. Recently, we also completed a national clinical trial of one of the first rational target inhibitors in relapsed DLBCL.
In addition, we have defined the unique molecular signature of mediastinal large B cell lymphoma (MLBCL), an unusual disease primarily affecting young women. Our studies uncovered unanticipated molecular similarities between MLBCL and classical Hodgkin's lymphoma, including a shared survival pathway, NFkappaB. Moreover, we identified three discrete subsets of DLBCLs - oxidative phosphorylation, B cell receptor/profileration, and host response (HR) - with unique transcriptional profiles and clinical and genetic features. The HR cluster shares features with the histologically defined T cell histiocyte-rich BCL, including a brisk immune/inflammatory cell infiltrate, fewer genetic abnormalities, younger age at presentation, and frequent splenic and bone marrow involvement.
Taken together, these new studies identify the tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets. Of note, both primary MLBCLs and HR DLBCLs exhibit constitutive NFkappaB signaling, highlighting the NFkappaB survival pathway as a promising rational therapeutic target.
Recent Awards
- Association of American Physicians,, 2005
- Doris Duke Distinquished Clinical Scientist Award, 2001
- Stohlman Scholar, Leukemia Society of America, 2000
- American Society of Clinical Investigation, 1996
- Scholar, Leukemia Society of America, 1995
Biography
Dr. Shipp received her MD in 1979 from Washington University School of Medicine, St. Louis, where she also completed an internship and residency in internal medicine as well as a research fellowship in immunology. She joined DFCI in 1986 and is currently the director of the Lymphoma Program for the Dana-Farber/Harvard Cancer Center. Her research focuses on the biology of normal and malignant B cells and diffuse large B cell lymphoma.
Select Publications
- Aguiar RC, Takeyama K, He C, Kreinbrink K, Shipp M. B-aggressive lymphoma (BAL) family proteins have unique domains which modulate transcription and exhibit PARP activity. J Biol Chem 2005;280:33756-65.
- Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G, Kurtin P, Pinkus GS, de Leval L, Harris NL, Savage KJ, Neuberg D, Habermann TM, Dalla-Favera R, Golub TR, Aster JC, Shipp MA. NFkappaB activity, function, and target gene signatures in primary mediastinal large B cell lymphoma and diffuse large B cell lymphoma subtypes. Blood 2005;106:1392-9.
- Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RCT, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA. Molecular profiling of diffuse large B cell lymphoma reveals discrete clusters including one characterized by host inflammatory response. Blood 2005;105:1851-61.
- Rodig SJ, Savage KJ, Pinkus GS, Shipp MA, Aster JC, Kutok JL. TRAF-1 expression and c-Rel activation distinguish classical Hodgkin's lymphoma from other morphologically or immunophenotypically similar forms of malignant lymphoma. Am J Surg Pathol 2005;29:196-203.
- Smith PG, Wang F, Wilkinson KN, Savage KJ, Klein U, Neuberg DS, Shipp MA, Aguiar RCT. The phosphodiesterase PDE4B limits c-AMP associated PI3K-AKT dependent, apoptosis in diffuse large B cell lymphoma. Blood 2005;105:308-16.
- LaCasce A, Howard O, Li S, Fisher D, Weng A, Neuberg D, Shipp MA. Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma 2004;45:761-7.
- Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, de Leval L, Kurtin P, Dal Cin P, Ladd C, Feuerhake F, Aguiar RCT, Li S, Salles G, Berger F, Jing W, Pinkus GS, Habermann T, Dalla-Favera R, Harris NL, Aster JC, Golub TR, Shipp MA. The molecular signature of mediastinal large B cell lymphoma differs from that of other diffuse large B cell lymphomas and shares features with classical Hodgkin's lymphoma. Blood 2003;102:3871-9.
- Takeyama K, Aguiar RCT, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA. The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem 2003;278:21930-7.
- Wilkinson K, Velloso ERP, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RCT. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood 2003;102:4187-90.
