PROJECT 1 : Molecular Genetics Chronic lymphocytic leukemia (CLL), an incurable disease that affects individuals over 50 years of age, is the most common leukemia in the Western World. At present, the clinical approach to the treatment of CLL is """"""""wait and watch"""""""" because in most cases the disease is indolent, often for long periods of time, although with time it may transform into an aggressive disease. Thus, it may be counterproductive to treat a disease that may remain indolent for long periods of time with aggressive chemo/immunotherapy. On the contrary, the aggressive form of CLL, that involves approximately 20-30% of patients, is a malignant disease with poor prognosis that should be treated promptly and aggressively. During the past few years, with the support of this grant and of interactions and collaborations with investigators of the other projects, we have discovered the fundamental genetic changes responsible for the indolent and aggressive forms of CLL. We were. also able to develop mouse models for both the aggressive and indolent forms of CLL. Recently we have compared the microRNA expression profiles in samples obtained from CLL patients that have remained indolent for many years, to samples obtained from CLL patients that were indolent but became aggressive with time and we have identified specific changes in microRNA expression that correlate with the malignant progression. In this renewal application, we intend unravel the fundamental changes that convert an indolent to an aggressive disease by the following aims:
AIM #1 Detection of the genome-wide microRNA alterations during the progression of CLL AIM #2 Studies of the molecular networks controlled by the altered microRNAs AIM #3 Identification of the factors promoting microRNAs dysregulation during the progression of CLL We also plan to exploit the mouse models we have developed with this grant support to unravel the mechanisms involved in tumor progression, thus facilitating an understanding of the progression of human CLL.
Chronic lymphocytic leukemia (CLL) is the most common leukemia of the Western World and is incurable. We propose to identify targets that can be exploited for the development of innovative therapy for the cure and prevention of this disease.
|Kashyap, Manoj K; Kumar, Deepak; Jones, Harrison et al. (2016) Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway. Oncotarget 7:2809-22|
|Lamothe, Betty; Wierda, William G; Keating, Michael J et al. (2016) Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses. Clin Cancer Res 22:4712-26|
|Oakes, Christopher C; Seifert, Marc; Assenov, Yassen et al. (2016) DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 48:253-64|
|Balatti, Veronica; Acunzo, Mario; Pekarky, Yuri et al. (2016) Novel mechanisms of regulation of miRNAs in CLL. Trends Cancer 2:134-143|
|Lampson, Benjamin L; Kasar, Siddha N; Matos, Tiago R et al. (2016) Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 128:195-203|
|Salzer, Elisabeth; Cagdas, Deniz; Hons, Miroslav et al. (2016) RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol 17:1352-1360|
|Dhar, Sachin; La Clair, James J; LeÃ³n, Brian et al. (2016) A Carbohydrate-Derived Splice Modulator. J Am Chem Soc 138:5063-8|
|Hawkins, Edwin D; Duarte, Delfim; Akinduro, Olufolake et al. (2016) T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 538:518-522|
|Sarkar, Aloke; Balakrishnan, Kumudha; Chen, Jefferson et al. (2016) Molecular evidence of Zn chelation of the procaspase activating compound B-PAC-1 in B cell lymphoma. Oncotarget 7:3461-76|
|Thompson, Philip A; O'Brien, Susan M; Xiao, Lianchun et al. (2016) Î²2 -microglobulin normalization within 6 months of ibrutinib-based treatment is associated with superior progression-free survival in patients with chronic lymphocytic leukemia. Cancer 122:565-73|
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