Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western hemisphere. Its clinical course is heterogeneous and difficult to predict;overall survival (OS) after diagnosis varies considerably (from <2 years to decades), making such predictions of utmost importance. Some patients diagnosed with Rai stage 0 (lymphocytosis of e5,000 B lymphocytes/?L) or 1 (lymphocytosis with lymphadenopathy) never need treatment;others progress rapidly. Generally accepted guidelines recommend starting treatment only after disease progression (characterized by development of anemia, or lymphadenopathy, among other signs). We and others have shown that an intricate interplay between abnormalities in protein-coding genes (PCGs) and non-coding RNAs (ncRNAs) is causally involved in CLL initiation, and progression. We hypothesize that the risk of progression is related to intrinsic biologic characteristics (e.g. expression of PCG or ncRNA from malignant B cells as well as from viral origin) of the CLL clone that exists early in the disease course. Thus, it should be possible to distinguish patients who are at risk of progression from patients with indolent CLL (defined as stable Rai stage 0/I disease not requiring therapy for e5 years after diagnosis). Patients diagnosed with any stage of CLL, before or after treatment, may undergo a Richter's transformation (RT);they develop an aggressive diffuse large B-cell lymphoma that is typically therapy resistant and associated with short OS. About 80-90% of RT is clonally related to the CLL clone. We hypothesize that the risk to develop RT is associated with intrinsic biologic characteristics of the CLL clone before transformation. Thus, it should be possible to identify those patients who are at risk of RT early in the disease course. None of the present used clinical markers can do this with high accuracy. This proposal's goal is to focus on this challenging subset of clinically early stage cases to identify expression signatures of coding and non-coding RNA transcripts, elucidate their roles in disease progression, and their clinical significance as biomarkers of early diagnosis. Our long-term goal is to find interactor pairs of microRNAs and target PCGs with key roles in the onset of disease, understand their mechanisms of action, and use the acquired knowledge to develop new diagnostic and prognostic tools.

Public Health Relevance

Chronic lymphocytic leukemia (CLL) is the most common leukemia and is characterized by a highly variable clinical outcome difficult to predict. We and others have shown that an intricate interplay between abnormalities in protein-coding genes (PCGs) and non-coding RNAs (ncRNAs) is causally involved in CLL initiation and progression. We hypothesize that disease progression and transformation are related to intrinsic biologic characteristics (e.g., expression of PCGs and ncRNAs of cellular and viral origin) of the CLL clone that exist in the earliest stages of disease course.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA182905-01
Application #
8629982
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Sorbara, Lynn R
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$573,195
Indirect Cost
$156,419
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Giza, Dana Elena; Vasilescu, Catalin; Calin, George A (2014) MicroRNAs and ceRNAs: therapeutic implications of RNA networks. Expert Opin Biol Ther 14:1285-93