Margaret A. Shipp, MD
Professor of Medicine, Harvard Medical School
Office phone: 617-632-3874
Preferred contact method: office phone
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Bone marrow transplantation, Lymphoma, Hodgkin disease
Area of ResearchResearch interests
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
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 at Barnes Hospital. Her research focuses on the biology of normal and malignant B cells and aggressive B-cell lymphomas. Dr. Shipp is the Chief of the Division of Hematologic Neoplasia at DFCI, the Director of the Lymphoma and Myeloma Program of the Dana-Farber/Harvard Cancer Center and a Professor of Medicine at Harvard Medical School.
- Distinguished Woman in Medicine and Science, Northwestern University School of Medicine, 2007
- 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
Our clinical and basic research group focuses on the pathogenesis and treatment of aggressive B-cell lymphomas, particularly the most common lymphoid malignancy, diffuse large B-cell lymphoma (DLBCL) and related variants and Hodgkin lymphoma. We previously led an international effort to identify highly reproducible clinical prognostic factors in patients with aggressive lymphoma (primarily DLBCL) and develop a model to predict patient outcome. Investigators from 16 major centers in the United States, Canada and Europe contributed data on over 3,000 patients to the International Prognostic Factors project and the subsequent development of the International Prognostic Index (IPI). The IPI is now used worldwide to assess the probability that a DLBCL patient will be cured with standard therapy or require more intensive, investigational treatment. In fact, most recent studies of risk-related therapy in DLBCL are based on IPI-defined patient subgroups. The IPI has also been widely applied to other lymphoid neoplasms.
Our laboratory is also characterizing molecular bases for the recognized clinical heterogeneity in DLBCL. Earlier studies focused on specific genes and pathways implicated in biology of normal and malignant lymphoid progenitors. For example, our group cloned and characterized one of the first lymphoid differentiation antigens associated with germinal center B-cells and a good risk subtype of DLBCL, CD10. We demonstrated that CD10 was a neutral endopeptidase that regulated peptide-mediated signaling, stromal cell dependent lymphopoiesis and B-cell reconstitution and maturation in vivo. More recently, our group has identified and characterized novel risk-related genes in DLBCL, including the B-cell protein tyrosine phosphatase, PTPROt, which regulates spleen tyrosine kinase (SYK) activity and is itself a BCL6 target, and 2 partner proteins, BAL and BBAP, which play unique roles in DNA damage repair. In addition, we have developed genome-wide approaches to define the unique molecular signatures of specific DLBCL subtypes and more rational therapeutic targets. Our pilot studies identified several signaling pathways associated with resistance to standard therapy. Two of these pathways (PKCbeta and PDE4B/cAMP) have now been credentialed as rational therapeutic targets in DLBCL. Clinical trials of an oral PKCbeta inhibitor in relapsed/refractory DLBCL are completed and studies in newly diagnosed DLBCL are underway.
Additional comprehensive analyses of the molecular signatures of large B-cell lymphoma subtypes led to the identification of discrete disease subtypes. In initial studies, we defined the unique molecular signature of MLBCL, an unusual disease primarily affecting young women. These studies uncovered an unanticipated molecular link between MLBCL and classical Hodgkin lymphoma and a shared NFkappaB survival pathway.
Thereafter, we defined three discrete subsets of DLBCLs: Oxidative Phosphorylation; B-cell Receptor/Proliferation (BCR); and Host Response (HR) tumors. HR tumors which were largely defined by their inflammatory/immune cell infiltrate and shared multiple features of histologically defined T-cell histiocyte-rich BCL. BCR-type DLBCLs, which overexpress BCL6 and have more frequent BCL6 translocations, exhibit coordinate regulation of BCL6 target genes and selective sensitivity to BCL6 inhibitors. BCR-type DLBCLs are reliant upon tonic B-cell receptor signaling and uniquely sensitive to targeted inhibition of this critical survival pathway with a spleen tyrosine kinase (SYK) inhibitor. These preclinical observations led to a recently completed national phase I/II clinical trial of an oral SYK inhibitor which exhibited clinical activity in relapsed/refractory DLBCL.
Our observations regarding the shared molecular features of MLBCL and classical Hodgkin lymphoma (cHL) prompted additional analyses of the defining features of cHL. In cHL, small numbers of malignant Reed-Sternberg (RS) cells reside within an extensive inflammatory infiltrate. We found that Hodgkin RS cells exhibit AP-1 dependent overexpression of galectin-1 (Gal1), a carbohydrate-binding lectin that selectively inhibits the apoptosis of cytotoxic T cells and Th1 cells, skews the balance toward a Th2 type cytokine profile and favors the expansion/retention of Treg cells. Gal1 represents a novel therapeutic target for restoring immune surveillance in cHL and several additional malignancies. For these reasons, we have now developed neutralizing Gal1 monoclonal antibodies for further clinical evaluation.
- 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.
- 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 lymphoma. Blood, Plenary paper, First Edition online 8/21/03 and 2003; 102:3871-9.
- Howard OM, Gribben JG, Neuberg DS, Kim HH, Poor C, Janicek MJ, Shipp MA. Rituximab and CHOP induction therapy for newly diagnosed mantle cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 2002; 20:1288-94.
- Aguiar RCT, Yakushijin Y, Kharbanda S, Tiwari S, Freeman GJ, Shipp MA. PTPROt: an alternatively spliced and developmentally regulated B-lymphoid phosphatase that promotes G0/G1 arrest. Blood 1999; 94:2403-13.
- Shipp M, Harrington D, Chairpersons. Anderson J, Armitage J, Bonadonna G, Brittinger G, Cabanillas F, Canellos G, Coiffier B, Connors J, Cowan R, Crowther D, Engelhard M, Fisher R, Gisselbrecht C, Horning S, Lepage E, Lister A, Neerwaldt J, Montserrat E, Nissen N, Oken M, Peterson B, Tondini C, Velasquez W, Yeap B. A predictive model for aggressive non-Hodgkins lymphoma: N Engl J Med 1993; 329:987-94.
- Shipp MA, Ross K, Tamayo P, Angelo M, Reich M, Weng AP, Kutok JL, Pinkus GS, Aguiar RCT, Ray TS, Gaasenbeek M, Neuberg D, Koval MA, Last KW, Norton A, Mesirov J, Lister TA, Lander ES, Aster JC, Golub TR. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.. Nat Med 2002; 8:68-74.
- Aguiar RCT, Yakushijin Y, Kharbanda S, Salgia R, Fletcher JA, Shipp MA. BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration. Blood 2000; 96:4328-34.
- Shipp MA, Vijayaraghavan J, Schmidt EV, Masteller EL, D'Adamio L, Hersh LB, Reinherz EL. Common acute lymphoblastic leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ("enkephalinase"): direct evidence by gene transfection analysis. Proc Natl Acad Sci USA 1989; 86:297-301.
- Shipp MA, Stefano GB, D'Adamio L, Switzer SN, Howard FD, Sinisterra J, Scharrer B, Reinherz EL. Down-regulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. Nature 1990; 347:394-6.
- 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 identifies robust subtypes including one characterized by host inflammatory response. Blood, Plenary Paper, First Edition online 11/18/04 and 2005; 105:1851-61.
- 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. NFkapppaB activity, function and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood, First Edition online 5/3/05 and 2005; 106:1392-9.
- 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, online 8/1/05 and 2005; 280:33756-65.
- Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, Nandula S, Aster JC, Cattoretti G, Murty V, Shipp MA, Dalla-Favera R. In activation of the PRDM1/BLIMP1 gene in non-germinal center type diffuse large B-cell lymphoma. J Exp Med 2006; 203:311-7.
- Chen L, Juszczynski P, Takeyama K, Aguiar RCT, Shipp MA. Protein tyrosine phosphatase receptor-type o Truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell receptor signaling and cellular proliferation. Blood 2006; 108:3428-33.
- Juszczynski P, Kutok JL, Li C, Mitra J, Aguiar RC, Shipp MA. BAL1 and BBAP are regulated by a gamma interferon-responsive bidirectional promoter and are overexpressed in diffuse large B-cell lymphomas with a prominent inflammatory infiltrate. Mol Cell Biol 2006; 26:5348-59.
- Rodig SJ, Savage, KJ, LaCasce AS, Weng, AP, Harris, NL, Shipp MA, His ED. Gascoyne RD, Kutok JL. Expression of TRAF1 and nuclear c-rel distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B cell lymphoma. Amer J Surg Path 2007; 31:106-12.
- Polo JM, Juszczynski P, Monti S. Cerchietti L, Ye K, Shipp M, Melnick A. A transcriptional signature with differential expression of BCL6 target genes accurately identifies BCL6-dependent diffuse large B-cell lymphomas. Proc Natl Acad Sci USA 2007; 104:3207-12.
- Robertson MJ, Kahl BS, Vose JU, de Vos S, Laughlin M, Flynn P, Rowland K, Cruz J, Goldberg SL, Musib L, Darstein C, Enas N, Kutok JL, Aster JC, Neuberg D, Savage KJ, LaCasce A, Thornton D, Slapak CA, Shipp MA. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed and refractory diffuse large B-cell lymphoma. J Clin Oncol 2007; 25:1741-6.
- Juszczynski P, Ouyang J, Monti S, Scott R, Takeyama K, Abramson J, Chen W, Kutok JL, Rabinovich GA, Shipp MA. The AP1-dependent secretion of Galectin-1 by Reed-Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA 2007; 104:13134-8.
- Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks and predicts response to ABT-737 in lymphoma cells. Cancer Cell 2007; 12:171-85.
- Takeyama K, Monti S, Manis JP, Dal Cin P, Getz G, Beroukhim R, Aster JC, Alt FW, Golub TR, Shipp MA. Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. Oncogene On-line 7/16/07 and 2008; 27:318-22.
- Chen L, Monti S, Juszczynski P, Chen W, Kutok JL, Shipp MA. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood On-line 1/15/07 and 2008; 111:2230-37.
- Rodig SJ, Ouyang J, Juszczynski P, Currie T, Law K, Neuberg DS, Rabinovich GA, Shipp MA, Kutok JL. AP1-dependent galectin-1 expression delineates classical Hodgkin and anaplastic large cell lymphomas from other lymphoid malignancies with shared molecular features. Clin Cancer Res 2008; 14:3338-44.
- Yan Q, Dutt S, Xu R, Manis JP, Shipp MA. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol Cell 2009; 36:10-20.
- Juszczynski P, Chen L, ODonnell E, Polo JM, Ranuncolo M, Dalla-Favera R, Melnick A, Shipp MA. BCL6 modulates tonic BCR signaling in diffuse large B-cell lymphomas by repressing the SYK phosphatase, PTPROt. Blood 2009;114(26):5315-21.
- Friedberg JW, Sharman J, Sweetenham J, Johnston, PB, Vose JM, LaCasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non Hodgkin lymphoma and chronic lymphocytic leukemia. Blood prepublished on line 11/17/09; DOI 10.1182/blood-2009-08-236471.
- Juszczynski P, Rodig SJ, Ouyang J, ODonnell E, Takeyama K, Mlynarski W, Mycko K, Szczepanski T, Gaworczyk A, Krivtsov A. Faber J, Sinha AU, Rabinovich GA, Armstrong SA, Kutok JL, Shipp MA. MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-bind protein, Galectin-1. Clin Cancer Res, in press.
- Juszczynski, Przemyslaw, MD, PhD
- Chapuy, Bjoern, MD
- Chen, Linfeng, PhD
- Yansheng, Hao, Ph.D
- Wang, Zhe, PhD
- Ouyang, Jing, PhD
- Green, Michael, PhD
- Yan, Qingsheng, PhD