Genetics Funded Projects

All cancers show abnormalities in their genetic code which contribute to the development of cancer and its clinical course. Each cell is exposed to external and toxic stress and suffers mutations or “mistakes” in the copying process of the genetic code, which will change the cell’s genome. While most of these mistakes will be silent or repaired, some of these mistakes alter critical genes, leading to a growth of cancer cells. There are several different genes which can be altered. This leads to various types and subtypes of cancer. The identification of genes that lead to aggressive disease or resistance to therapy is a central aim of cancer research. While mutations of key tumor suppressors (genes that normally prevent cancer formation; e.g.ATM, TP53) are known, a precise map of mutations of the CLL genome is currently missing.

We hypothesize that critical genes are targeted by mutations during the disease course and lead to particular disease characteristics. Novel methods of analyzing samples will allow us to decipher the genetic code of CLL to understand which changes are driving refractory CLL. Modern sequencing technology holds potential to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks. These insights will identify the mutational signatures associated with different disease courses of CLL. We thus hope to answer key clinical questions necessary to move CLL research forward.

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The presence of an extra copy of chromosome 12 (+12) occurs in approximately 20% of CLL patients.  The appearance and expression of proteins on CLL cells in cases with +12 is often atypical compared to CLL cases without +12.  In addition, patients whose CLL cells have +12 often have a poorer prognosis compared to patients whose CLL cells have deletions in chromosome 13 (13q-), the most common chromosomal abnormality in CLL. A generous amount of information has been discovered regarding abnormalities in chromosome 13. However, there are few studies that have attempted to identify the critical genes that contribute to the more aggressive behavior of cases with +12.

The goal of this project is to identify genes (protein-coding and microRNAs genes) that are differentially expressed in CLL cases with +12, compared to cases with 13q- and those with no abnormalities.  The information gathered may identify biological targets that contribute to the more aggressive clinical behavior of +12 and may form the basis for future individualized therapeutic approaches.

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Despite the frequency of chronic lymphocytic leukemia (CLL) and decades of research, its molecular architecture still remains a mystery. However, recent discoveries will soon change our knowledge of CLL. A new class of genes called microRNAs (miRNAs), a type of small, non-coding gene with regulatory functions, has been found to be profoundly altered in the majority of CLL patients.

The purpose of this project is to decipher if miRNAs in plasma/serum (the liquid part of the blood in which cells are suspended) of CLL patients could be used as: 1) diagnostic and prognostic markers, 2) markers of response to therapy and 3) markers of residual disease or recurrence. The specific focus for this project is to determine the levels of miRNAs in the plasma/serum in large sets of CLL patients.
Plasma/serum is easily obtainable from patients for both research and clinical purposes, as it can be collected through minimally invasive blood tests. This will be the first study focusing on the identification of the clinical significance of the miRNA levels in plasma/serum in CLL patients. If successful, the study results could lead to a useful new diagnostic tool.

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CLL results from an accumulation of B-cells that have defects in controlling cell death and proliferation. Our previous research helped to demonstrate that there are a series of mechanisms which keep CLL cells alive (pro-survival mechanisms) and signal the cells to continue multiplying (pro-proliferative mechanisms). This was shown in CLL cases with abnormalities of chromosome 13. Our present research efforts are directed at revealing an additional mechanism that is potentially involved in the multistep development of CLL.

There is increasing evidence that CLL cells become incapable of following the normal route of B-cell differentiation – the process of becoming a more specialized cell. It was recently found that Interferon Regulatory Factor 4 (IRF4), a gene which is part of the multistep process of normal B-cell differentiation, is associated with CLL development. We hypothesize that CLL cells fail to produce enough IRF4 needed to function normally. This subsequently arrests the CLL cells in their current developmental stage. This developmental block further exacerbates the cellular imbalance created by the loss of control of cell death and proliferation, resulting in tumor cell accumulation.

Our present proposal is aimed at understanding the biological consequences and mechanisms of reduced IRF4 expression in CLL. By deleting the IRF4 gene in mouse models, we can better understand the gene’s role in CLL cells and determine the extent to which IRF4-deletion accelerates CLL development. Clarifying the mechanisms that disrupt the normal differentiation path of the CLL cells is expected to guide the development of innovative therapeutic strategies for CLL treatment.

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