Functional genomic studies in experimental tumor models to guide molecular and cellular therapy of patients with B-cell lymphoma

We are interested in the study of the genetic networks that drive malignant transformation in the different B-cell lymphomas. In particular, we try to discover what genes are critical for tumor initiation and maintenance and thus may serve as effective targets for directed therapies. In initial studies, integration of the genomic and transcriptomic profiles of a large series of human lymphoma cell lines and primary tumors led us to the identification of novel genes possibly involved in lymphoma pathogenesis. To determine the function, regulation and interaction of these genes in normal and neoplastic B cells, we are performing functional genomics studies combined with molecular therapeutic assays in human cell lines and genetically manipulated mice that develop human-like lymphomas. Using these experimental models we also try to learn whether lymphomas, similarly to leukemias and some solid tumors, originate from hematopoietic stem cells upon mutation (cancer stem cells) or they derive from more committed progenitors or even mature lymphoid cells. In summary, our major goal is to broad our knowledge of lymphoma biology to advance towards more effective directed therapies of patients with lymphoma.

A more detailed description of the major ongoing projects in the lab follows:

Search for key target genes through therapeutic manipulation of oncogenes in human cell lines and mouse models of lymphoma. To address this issue, we have selected mantle cell lymphoma (MCL) as a model disease because of its very poor prognosis. We have developed a transgenic mouse for CCDN1/Cyclin D1 oncoprotein where its expression can be externally regulated. These mice are being crossed with other mouse strains carrying mutations in genes involved in human MCL pathogenesis. Upon tumor development, we are testing the reversibility of the different genetic subgroups of lymphoma either by switching off Cyclin D1 expression or by using various anti-Cyclin D1 compounds. Initial data point out that regression of lymphomas after Cyclin D1 inactivation primarily relies on the pattern of secondary mutations. We expect to translate these data into the design of rational clinical trials using novel anti-Cyclin D1 drugs in patients with MCL.  

NF-kB signalling pathway as a target for therapy in B-cell lymphomas. To evaluate this hypothesis, we have selected two different lymphoma subgroups with constitutive activation of NF-kB: MALT lymphoma and cell activated diffuse large B-cell lymphoma (ABC-DLBCL). Using different models of transgenic mice for NF-kB activating genes involved in MALT lymphoma pathogenesis (MALT1, BCL10 and API2-MALT1), we have demonstrated that MALT1 shows oncogenic properties in vitro and in vivo, and thus may serve as a target for therapeutic interventions. In ABC-DLBCL we aim to unravel the roles of the transcription factor FOXP1 as well as the FOXP1-target genes by functional genomic analysis of human cell lines and genetically manipulated mice. More basic research projects include the functional characterization of the P53-inducible gene LITAF in germinal center lymphomas; the role of BIM inactivation in the resistance to chemotherapy of patients with Burkitt lymphoma; the molecular characterization of the chromosome 7q32 deletion in splenic marginal zone lymphoma; the tumorigenic potential of a novel homeobox gene in marginal- zone derived lymphomas; and the involvement of the miR-17-92 cluster in normal B-cell development and germinal center B-cell lymphoma generation.

Stem cells and lymphoma development. Despite the identification and characterization of the cancer stem cells in leukemias and some solid tumors, the existence of similar originating cells in the different B-cell lymphomas remains largely unexplored. Our laboratory has recently embarked in the investigation of the “cancer stem cell hypothesis” in lymphoma. We have focused on the study of two major subgroups of lymphoma, follicular lymphoma and mantle cell lymphoma. Using a classical approach, we are sorting various cell populations from human lymphoma biopsies and cell lines as well as from transgenic BCL2 and CCDN1/Cyclin D1 mouse models that develop human-like lymphoma. Then we measure the oncogenic capacity of the different isolated cell populations in immunodeficient mice. These experiments will determine what cells can originate lymphoma upon mutation, an important issue that may guide molecular therapies against these cells. Finally, we are also working in the molecular and functional characterization of the progenitor cells of origin of breast cancer that are isolated through the culture of mamosferes.