Department of Pathology
Boston Children's Hospital
Enders Building, Room 1116.1
300 Longwood Ave.
Boston, MA 02115
Tel: (617) 919-2662
Fax: (617) 730-0148
My laboratory is interested in the mechanisms of initiation, growth and therapy of hematologic cancers. In the past years, I have been working on different types of hematologic and solid cancers. Most lymphomas, but also an increasing number of solid tumors, are characterized by defined chromosomal translocations. The products of such translocations control tumor growth and confer precise biological characteristics to the tumors. Ultimately, they can be targeted by specific therapies. In lymphoma, translocations involving the Anaplastic Lymphoma Kinase (ALK) gene are characteristic of a subset of T cell lymphoma, the Anaplastic Large Cell Lymphoma (ALCL). However, recently they were found also in Non-Small Cell Lung Cancers (NSCLC) and other solid tumors. We have extensively studied the role of ALK in lymphoma and discovered multiple pathways essential to induce cellular transformation. By xenografts and mouse models, we want to define relevant mechanisms of ALK-mediated transformation in vivo but also to explore therapeutic approaches to target ALK in such cancers. We are currently exploiting innovative therapies such as ALK inhibitors, ALK-targeted siRNA and ALK-directed cancer immunotherapy. In this context, we developed a vaccination protocol that generates a strong ALK-specific anti-cancer immune response, and seek to explore its potential use in clinical settings.
Another main focus of the lab is to elucidate the mechanisms that govern the formation of chromosomal translocations in normal and neoplastic cells. In collaboration with Dr. Fred Alt, we developed a method to map translocations at a genome-wide level in normal primary B cells. By extending this and other genome-wide methods to T cells and other cell types, we aim at defining general rules for translocation formation, focusing on how transcription, DNA Double Strand Breaks (DBSs) availability and position, tissue specificity and other nuclear or DNA repair factors can influence the type and the frequency of translocations found in human cancers.
One more line of research in the lab is devoted to the discovery of novel genetic lesions in lymphoma and solid tumors, by innovative techniques of next-generation sequencing. In particular, we recently co-discovered mutations in FBXO11, a gene involved in the degradation of BCL6 in human lymphomas. We aim at expanding these findings to other lymphomas or solid tumors, and at generating mouse models to uncover the roles of these genes in normal B cell development and lymphoma formation.
Chiarle R, Simmons WJ, Cai H, Dhall G, Zamò A, Raz R, Karras J, Levy DE , Inghirami G. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med. 2005;11(6): 623-629. Highlighted in Nat Med. 2005 Jun;11(6):595-6.
Chiarle R, Martinengo C, Mastini C, Ambrogio C, D’Escamard V, Forni G, Inghirami G. Anaplastic Lymphoma Kinase is an effective oncoantigen for lymphoma vaccination. Nat Medicine. 2008 Jun;14(6):676-80.
Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008 Jan;8(1):11-23. Highlighted on the Nat Rev Cancer cover
Gostissa M, Alt FW, Chiarle R. Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu. Rev. Immunol. 2011 Apr 23;29:319-50.
Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, Ho Y, Myers DR, Choi VW, Compagno M, Malkin DJ, Neuberg D, Monti S, Giallourakis CC, Gostissa M, and Alt FW. Genome-Wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells. Cell 2011 Sep 30;147(1):107-19. Highlighted on the Cell cover and in Cell. 2011 Sep 30;147(1):20-2 and in Nat Rev Genet. 2011 Nov;12(11):741.
Duan S, Cermak L, Pagan J, Rossi M, Martinengo C, Francia di Celle P, Chapuy B, Shipp M, Chiarle R*, and Pagano M*. FBXO11 targets BCL6 for degradation and is inactivated in Diffuse Large B-Cell Lymphomas. Nature, 2012 Jan 5;481(7379):90-3.
Last Update: 1/6/2014