Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma (B- NHL), accounting for 30-40% of the de-novo diagnoses and also arising as a frequent clinical evolution of follicular lymphoma (FL). Despite remarkable advances in both diagnosis and treatment, DLBCL remains a significant clinical challenge, as nearly 50% of patients are not cured by available therapeutic approaches. Major efforts are needed toward the identification of the molecular mechanisms that are responsible for disease development and maintenance, and can be therapeutically targeted. Recent analysis by us (Pasqualucci et al., Nature 2011;Pasqualucci et al., Nature Genetics 2011) and others (Morin et al., Nature 2011) using genome-wide approaches including next generation whole-exome sequencing and high-density single nucleotide polymorphism array analysis have characterized the landscape of genomic lesions that are associated with DLBCL, and have led to the identification of recurrent structural alterations in multiple histone/chromati remodeling genes. Among the recently discovered genetic lesions, the MLL2 histone H3K4 trimethyltransferase emerged as the most common target. Overall, ~30% of DLBCL and 89% of FL patients display somatic point mutations that remove the C-terminal enzymatic domain of MLL2, leading to its inactivation (Pasqualucci et al., Nature Genetics 2011;Morin et al., Nature 2011). The extremely high frequency of these lesions and their clearly disruptive nature in DLBCL and FL, the two major subtypes of B- NHL (combined, up to 70% of all diagnoses) indicate a central role for MLL2 in the pathogenesis of these malignancies. Building on these results, the general goal of this project will be to elucidate the normal and pathologic function o MLL2 in B cells, with the following Specific Aims: i) characterize the full spectrum of genetic and epigenetic mechanisms of inactivation affecting MLL2 and its paralogue MLL3 in DLBCL and FL;ii) identify the transcriptional network that is regulated by MLL2 in normal B cells, and is disrupted in DLBCL as a consequence of MLL2 inactivating mutations;iii) examine the role of MLL2 deficiency in lymphomagenesis in vivo, alone or in cooperation with two additional genetic lesions that are found recurrently associated with MLL2 mutations in the human tumors, namely chromosomal translocations of the proto-oncogenes BCL2 and BCL6. The results obtained from the proposed studies are expected to provide i) significant new information toward our understanding of the mechanistic factors that underlie the pathogenesis of these two common B- NHLs, ii) mouse models of MLL2-driven lymphomagenesis that may serve for preclinical therapeutic targeting;iii) insights into novel therapeutic approaches, thus paving the basis for further advancements in disease prevention and treatment.

Public Health Relevance

This research proposal aims at identifying the molecular circuitry regulated by MLL2 in normal and transformed mature B cells, and at elucidating the role of MLL2 inactivation in the development of follicular lymphoma and diffuse large B-cell lymphoma, the two most common forms of human lymphoma. The results of these studies are expected to improve our understanding of the pathogenesis of these common cancers, and to provide new insights for the development of better diagnostic and therapeutic tools.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Howcroft, Thomas K
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Pasqualucci, Laura; Khiabanian, Hossein; Fangazio, Marco et al. (2014) Genetics of follicular lymphoma transformation. Cell Rep 6:130-40
Fabbri, Giulia; Khiabanian, Hossein; Holmes, Antony B et al. (2013) Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med 210:2273-88
Pasqualucci, Laura (2013) The genetic basis of diffuse large B-cell lymphoma. Curr Opin Hematol 20:336-44
Ying, Carol Y; Dominguez-Sola, David; Fabi, Melissa et al. (2013) MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 14:1084-92