Acute leukemia, both of myeloid and lymphoid origin, is a very prevalent cancer in kids and adults. Unfortunately, frontline radiation and chemotherapy causes lasting cognitive problems and can also lead to secondary cancers. Additionally, about one-fourth of children and 50% of adults with acute leukemia develop resistance to therapy or relapse post therapy.
Mechanisms of resistance are poorly understood and current research on oncogenesis (the development of cancer) mainly focuses on alterations (mutations) of gene units in leukemia. Recent studies show that aberrant patterns of transcripts - pieces of RNA stitched together via a process called splicing - are critical factors in oncogenesis.
I have discovered that proteins controlling transcript stitching are aberrantly stabilized and have identified that this leads to abnormal splicing patterns. This phenomenon creates generations of transcripts not found in normal cells, ultimately leading to resistance to therapy. I aim to define mechanisms of therapy resistance related to transcript stitching and protein stability in high-risk leukemia by directly comparing therapy-responsive or resistant leukemia cases to each other and to healthy samples. I will also suggest therapeutic platforms for patients using relevant models of disease that can translate to clinical trials. This approach is at the heart of personalized medicine, as it takes into consideration protein levels for candidate proteins to target drug resistance.