Research Faculty

Address
1130 St Nicholas Ave, room 507B
New York, NY 10032

Phone: 212-851-5248
Fax: 212-851-5256

lp171@cumc.columbia.edu
Education and Training
University of Perugia Medical School (M.D.);
Columbia University (post-doctoral training)

Affiliation
Institute for Cancer Genetics

Training Activities
Cancer Genetics
Cancer Biology
Laura Pasqualucci, MD
Professor of Pathology and Cell Biology at CUMC
Research Summary

The research focus of our group has been in elucidating the genetic basis of mature B cell malignancies, with emphasis on the two most common subtypes, diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Analogous to other cancers, the pathogenesis of lymphoma entails the accumulation of multiple genetic lesions in key signaling pathways and transcription factors that are central to the biology of its normal cell counterpart during the germinal center (GC) reaction. GCs represent a unique microenvironment where B cells proliferate at high rate while sustaining physiologic DNA remodeling events required for the production of high-affinity antibodies, without eliciting DNA damage responses. Shifts in the delicate balance governing these potentially dangerous events constitute a major driver of lymphomagenesis. Our general goal is to elucidate the function and the molecular mechanisms by which lymphoma-associated genetic lesions contribute to the malignant transformation of GC B cells, as a pre-requisite for the development of more effective therapies. In particular, we are taking advantage of complementary approaches integrating high-throughput genomic analyses, biochemical assays and genetically-engineered mouse models to i) identify genes and pathways that are disrupted by genetic alterations in these tumors; ii) elucidate their role during normal B cell development, and iii) dissect the mechanisms by which genetics-driven deregulation of their function contributes to the initiation and maintenance of cancer. Special emphasis is placed on the role of histone/chromatin modifiers, including the H3K4 methyltransferase KMT2D and the acetyltransferases CREBBP and p300, which we identified in recent whole-exome sequencing studies as the most common targets of mutations in both FL and DLBCL. These lesions represent early events during the history of tumor clonal evolution and suggest a prominent role for chromatin dysregulation in the development of lymphoma, where they may contribute to the initial phases of oncogenic transformation by remodeling the epigenetic landscape of the precursor cancer cell.
Service Activities

Lymphoma Research Foundation, National Cancer Institute, NIH
Selected Publications

Zhang J, Vlasevska S, Wells VA, Nataraj S, Antony AB, Duval R, Meyer SN, Mo T, Basso K, Brindle PK, Hussein S, Dalla-Favera R, Pasqualucci L. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B cell lymphoma. Cancer Discovery, 2017; Jan 9. pii: CD-16-1417. doi: 10.1158/2159-8290 [Epub ahead of print].

Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, Vlasevska S, Mo T, Tang H, Basso K, Ge K, Dalla-Favera R, Pasqualucci L. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nature Medicine 2015; 21(10):1190-8. PMID: 26366712

Pasqualucci L*, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, Ouillette P, Trifonov V, Rossi D, Tabbò F, Ponzoni M, Chadburn A, Murty VV, Bhagat G, Gaidano G, Inghirami G, Malek SN, Rabadan R, Dalla-Favera R*. Genetics of Follicular Lymphoma Transformation. Cell Reports, 2014; 6(1): 130-140. PMCID: PMC4100800. (*corresponding authors)

Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Hussein S, Bansal M, Califano A, Pasqualucci L, Basso K, Dalla-Favera R. MEF2B mutations lead to deregulated expression of the BCL6 oncogene in Diffuse Large B cell Lymphoma. Nature Immunology, 2013; 14(10):1084-1092.

Pasqualucci L*, Dominguez-Sola D, Chiarenza A, Fabbri A, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, Rossi D, Chadburn A, Murty VV, Mullighan CG, Gaidano G, Rabadan R, Brindle PK and Dalla-Favera R*. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature, 2011; 471(7337):189-195. (*corresponding authors)

Pasqualucci L*, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R*. Analysis of the coding genome of diffuse large B cell lymphoma. Nature Genetics, 2011; 43:830-837, 2011. (*corresponding authors)

Challa-Malladi M, Lieu YK, Califano O, Holmes A, Bhagat G, Murty VV, Dominguez-Sola D, Pasqualucci L*, Dalla-Favera R*. Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell, 2011; 20(6): 728-740. (*equal contribution)

Mandelbaum J, Bhagat G, Tang H, Mo T, Grunn A, Brahmachary M, Shen Q, Chadburn A, Rajewsky K, Tarakhovsky A, Pasqualucci L*, Dalla-Favera R*. Blimp1 is a tumor suppressor gene frequently disrupted in activated B-cell like diffuse large B cell lymphoma. Cancer Cell, 2010; 18(6):568-579. (*equal contribution).

Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, Bertoni F, Ponzoni M, Scandurra M, Califano A, Bhagat G, Chadburn A, Dalla-Favera R, Pasqualucci L. Mutations in multiple genes cause deregulation of the NF-B pathway in diffuse large B-cell lymphoma. Nature, 2009; 459(7247):717-721.

Pasqualucci L*, Bhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, Honjo T, Morse HC 3rd, Nussenzweig MC, Dalla-Favera R*. AID is required for germinal center-derived lymphomagenesis. Nature Genetics, 2008; 40:108-112. (*corresponding authors).

Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RSK, Küppers R, Dalla-Favera R. Hypermutation of multiple proto-oncogenes in B-cell Diffuse Large Cell Lymphomas Nature, 2001; 412: 341-346.

For full bibliography at http://www.ncbi.nlm.nih.gov/pubmed/?term=pasqualucci-L, please click the blue button below:

Current Projects

Current areas of investigation include the functional characterization of KMT2D and CREBBP/p300 in normal B cell development, the dissection of epigenetic mechanisms of lymphomagenesis that are driven by mutations in these genes, and the in vivo modeling of these alterations in the mouse, alone or in cooperation with other genetic lesions that are recurrently found in FL and DLBCL. We also use high-throughput genomic analyses to identify novel structural alterations associated with distinct prognostic categories of mature lymphoid malignancies, including follicular lymphoma transformation and chemoresistant diffuse large B cell lymphoma.

Committees , Council, and Professional Society Memberships

American Society of Hematology
American Association of Cancer Research
Keywords

Lymphoma, cancer genomics, germinal center transformation, epigenetic dysregulation


top
 
 
Contact the Pathology Webmaster at PathWebMaster@columbia.edu