Identification of biomarkers and possible therapeutical targets in B-cell lymphoproliferative disorders

Abstract

The main objective of this proposal is the development of studies that aggressively seek possible biomarkers and therapeutic targets four frequent B-cell lymphoproliferative disorders: multiple myeloma (MM), diffuse large B-cell lymphomas (DLBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The subproject 1 aims at identifying mutations JAK/STAT pathway genes and possible targets for the use of inhibitors of tyrosine-quinases in MM. The subproject 2 is an offshoot of the work initiated during the Clinical Cancer Genome Project, trying to assess the correlation between cancer/ testis antigens, that are possible targets for immunotherapy in MM, and some of T lymphocyte sub- populations that can have key role in regulating the response of MM patients to this type of intervention. The subproject 3 is the unfolding of another work developed during the Clinical Cancer Genome Project and attempt to assess the role of two genes still not well explored in MM (P53CSV and HSP70), that may represent targets for this disease. In the subproject 4, analysis of proteins expressed in the membranes of plasma cells, stromal and mononuclear cells present in MM bone marrow microenviroment by ESI QTOF MS technique (electrospray ionization quadrupole time of flight mass spectrometry) would be helpful in the discovery of new therapeutic targets in MM, a still uncurable disease. In the subproject 5, we explore the role of microRNAs (miRNAs) involved in the process of angiogenesis in DLBCL to assess their potential as therapeutic targets. In the sub-project 6, we will evaluate the profile of miRNAs in a newly described Epstein-Barr virus related diffuse large B-cell lymphoma of elderly, characterized by unfavourable clinical evolution. The subproject 7 will evaluate the frequency of monoclonal B-cell lymphocytosis (MBL) in pure Japanese descendent population resident in Brazil. These findings may be helpful in understanding the relationship between MBL and CLL and also clarify the pathogenesis and natural history of CLL. In the subproject 8 we will evaluate if halofuginone cytotoxicity in mantle cell lymphoma (MCL) is mediated by inhibition of Akt and NF-ºB signaling pathways. This hypothesis, if confirmed, could elucidate the mechanisms of antitumoral action of halofuginone and substantiate its rational combination with other classes of drugs as a new therapeutic strategy for MCL. Keywords: multiple myeloma; non-Hodgkin's lymphomas; chronic lymphocytic leukemia; diagnosis; treatment; prognosis; translational research; gene expression; Epstein-Barr virus; microRNA; angiogenesis; proteomics; molecular markers; potential therapeutic targets. (AU)