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UBC Theses and Dissertations

Mechanisms of acute leukemia disease initiation and maintenance through manipulation of IGF1R and RUNX family members. Jenkins, Catherine Elfi Sarah


Characterization of new pathways in Acute Myeloid Leukemia and T-cell Acute Lymphoblastic Leukemia which contribute to oncogenesis is necessary to relieve dependence on conventional chemotherapy for treatment of these diseases. In this dissertation, I characterized the role of signaling molecules (IGF1R) and transcription factors (RUNX1, RUNX3, NOTCH1) in regulating mechanisms of leukemia initiation and maintenance. I discovered that committed myeloid progenitor cells with genetically reduced levels of IGF1R were less susceptible to myelogenous leukemogenic transformation due, at least in part, to a cell-autonomous defect in clonogenic activity. Genetic deletion of IGF1R by inducible Cre recombinase however had no effect on growth/survival of established leukemia cells. I raise the possibility that IGF1R inhibitors in clinical development may be acting through alternate/related pathways. Second, in a retroviral insertional mutagenesis study, I cloned retroviral integration sites from hNOTCH1ΔE mouse leukemias to find genes which collaborate with Notch signaling in T-ALL initiation. Common integration sites include the previously identified Ikzf1, and a novel potentially Notch-collaborating gene, Runx3. Using a multicistronic lentiviral system, I show that RUNX1A, RUNX1B and RUNX3 were able to collaborate with the ΔEΔL allele of NOTCH1 to initiate leukemia. Finally, I sought to understand how RUNX1 and RUNX3 contribute to the biology of established T-cell leukemias. I found that both RUNX1 and RUNX3 contribute to T-ALL cell proliferation and survival. Although RUNX3 can induce cell proliferation, RUNX1 expression is finely tuned with overexpression and knockdown resulting in negative growth phenotypes. This may be in part to regulation of MYC, IL7R, IGF1R, and CDKN1B as well as affecting genome-wide H3K27Ac. I found that RUNX1 expression was targeted by the CDK7 inhibitor, THZ1. RUNX1 and RUNX3 are mediators of Notch-directed regulation of PKCθ, and as such are indirect regulators of LIC-activity. Finally, I showed that RUNX1 and Notch signaling provide complimentary, additive signals for growth of T-ALL cells. These experiments provide insight into the role of RUNX1 mutations in T-cell leukemia and point to a complementary role in supporting the Notch pathway.

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