2014 ACS-IRG Awardee Project Descriptions
Description: Fusion genes are a common occurrence in cancer. With new genetic engineering technology that is currently being developed, it is becoming possible to identify what genes and genetic pathways are being activated by such cancer-causing fusion genes genome-wide. This project seeks to identify the targets of the protein encoded by the NUP98-HOXA9 fusion gene with the aid of a novel genetic technology called “Calling Cards.” Calling Cards utilizes cellular machinery that is native to the cell, namely transposons and transposases. Transposons make up a majority of what has been labeled “junk DNA” in the past, and transposases are proteins that can cut and paste transposons in the genome. This technique enables us to map all the genes bound and activated by the product of NUP98-HOXA9 in a relatively simple procedure by using engineered transposons and transposases. Ultimately, this study may uncover targets for AML treatment and help understand the process by which leukemogenesis occurs.
Description:Cancer is the most common cause of death by disease in children, but is not primarily driven by acquired DNA mutations or exposures to toxic substances. We believe that children who develop cancer are born with a combination of damaging genetic changes. We have tested this by sequencing every gene in non-cancer DNA from 25 pairs of mothers and their infants who developed leukemia during the first year of life. Infant leukemia is the deadliest of all pediatric leukemias with a survival rate of less than 50 percent. We asked if these children possessed an increased amount of damaging genetic changes in genes already associated with leukemia. Compared to their mothers, unaffected children and all other genes in their DNA, the infants who developed leukemia possessed a significant excess of damaging genetic variation in leukemia-associated genes. We also found that in every infant with AML and half with ALL, there was one gene, MLL3, which showed a damaging genetic variant inherited from mother and from father. These results suggest that these infants are indeed born with an excess of inherited damaging genetic changes and that dysfunction of MLL3 may play a large role in the origins of infant leukemia. To further explore these observations, we will create white blood cells from engineered stem cells derived from actual patient skin cells. We will replace dysfunctional MLL3 with normal MLL3 gene via targeted genetic engineering and characterize behavior of all resulting cell lines in the presence and absence of toxic compounds that promote leukemia formation.
Description: Lymphoma is a blood cancer that arises from B cell, a kind of white blood cell that produces antibodies. The two major types of lymphoma are Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). Of all NHL, diffuse large B cell lymphoma (DLBCL) is the most common type and considered very difficult to treat. There are three different forms of DLBCL and the most aggressive form is called Activated B Cell–like DLBCL (ABC DLBCL). Patients with ABC DLBCL generally respond poorly to standard chemotherapy. Therefore it is important to develop newer drugs tailored towards the unique cancer-causing genes that underlie ABC DLBCL. We recently discovered that activating mutations of a gene, called MyD88, is present in 39% of ABC DLBCL, >95% of Waldenstrom’s macroglobulinemia and many other types of B cell malignancies. Mutated MyD88 produces an abnormal form of MyD88 protein that aberrantly activates multiple stimulatory signals within the cancer cells to promote cancer formation. My proposal aims at understanding how these MyD88 mutant proteins function and finding ways to block their activity. Based on my preliminary studies, I proposed that these abnormal MyD88 proteins may allow lymphoma cells to become hyper-responsive to the surrounding DNAs and RNAs, which in essence mimic the process in autoimmune diseases such as lupus and rheumatoid arthritis. From the therapeutic standpoint, I have identified an important “co-conspirator”, IRAK4, that MyD88 mutants critically rely on to promote cancerous growth. In this proposal, I introduce a new IRAK4 inhibitor as a novel therapeutic agent in MyD88-mutated lymphoma.
Description: Cervical cancer is the second most common cancer in women worldwide. Prevention and early treatment, specifically in resource poor areas continue to be problematic. A recent study has suggested that use of an intrauterine device (IUD), a long-acting contraceptive device, may reduce a woman’s risk of cervical cancer. The reasons why this might be have not yet been explored. This pilot study would like to explore 2 possible mechanisms. Nearly all cervical cancer can be attributed to high-risk human papilloma virus (HPV). We will investigate if IUD users have differing rate of high-risk HPV from non-IUD users. We will also look closely at those that test positive for HPV to determine if IUD users clear the virus more efficiently than non-IUD users. Lastly, we will compare the levels of inflammatory markers in the fluid around the cervix between the two groups. We suspect that IUD users will have higher levels of these markers creating an environment in which foreign substances (HPV) will be more readily detected and cleared by the body.