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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Barr, Paul M; Robak, Tadeusz; Owen, Carolyn et al. (2018) Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 103:1502-1510
Kondo, K; Shaim, H; Thompson, P A et al. (2018) Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 32:960-970
Hasan, Md Kamrul; Yu, Jian; Widhopf 2nd, George F et al. (2018) Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood 132:170-178
Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:
Gribben, John G (2018) How and when I do allogeneic transplant in CLL. Blood 132:31-39
Sivina, Mariela; Werner, Lillian; Rassenti, Laura et al. (2018) Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation. Br J Haematol 180:597-600
Ott, Christopher J; Federation, Alexander J; Schwartz, Logan S et al. (2018) Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia. Cancer Cell 34:982-995.e7
Balatti, Veronica; Tomasello, Luisa; Rassenti, Laura Z et al. (2018) miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood 132:2179-2182
Vangapandu, Hima V; Chen, Huiqin; Wierda, William G et al. (2018) Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells. Leuk Lymphoma 59:1427-1438
Yu, Jian; Chen, Yun; Chen, Liguang et al. (2018) Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma. Oncotarget 9:24731-24736

Showing the most recent 10 out of 562 publications