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Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Collaborative Specialization

Developmental Biology

Supervisor

DeKoter, Rodney P.

Abstract

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated mice had 100% incidence of pseudokinase domain mutations in Jak1 or Jak3. These results indicate that tumours in treated mice develop later in life but become more aggressive than control tumours and that JAK mutations may act as drivers of leukemogenesis in the presence of lower levels of ROS.

Summary for Lay Audience

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent cancer occurring in young children and remains a leading cause of childhood death. B-ALL is associated with mutations in genes that are necessary for the development of B cells as well as high levels of reactive oxygen species (ROS). ROS are highly reactive molecules that can be blocked by chemicals known as antioxidants. High levels of ROS in cells can cause mutations in DNA, so we tested the ability of the antioxidant N-acetylcysteine for its ability to reduce the frequency of mutations in a mouse model of B-ALL. We found that treatment of mice with N-acetylcysteine did not increase survival of our mice, but that it did significantly change the biology of the tumours that formed. Tumours in treated mice started developing later in life compared to control mice and had differences in the level of expression of genes that are involved in B cell development, regulation of cell death, and cancer. Since tumours in treated mice started developing later in life, but still resulted in death at the same time as control mice, the tumours in treated mice may be more aggressive once they do develop. Analysis of the mutations in these tumours suggested that mutations in Jak genes may be necessary for the development of leukemia in treated mice, as they were found in 100% of the treated tumours. In conclusion, we have shown that N-acetylcysteine can delay the development of leukemia, but that it cannot prevent it.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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