Towards a B-Lymphoid Model of E2A-PBX1-Mediated Leukemogenesis: Evaluating the Impact of Hematopoietic Cell of Origin on the Transformation Properties of a Leukemogenic Transcription Factor

dc.contributor.authorWoodcroft, Marken
dc.contributor.departmentPathology and Molecular Medicineen
dc.contributor.supervisorLeBrun, David P.en
dc.date2013-09-03 00:09:29.299's University at Kingstonen
dc.descriptionThesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-09-03 00:09:29.299en
dc.description.abstractThe t(1;19) chromosomal translocation is present in 5% of acute lymphoblastic leukemia (ALL) cases and leads to expression of the oncogenic transcription factor, E2A-PBX1. Although t(1;19) is exclusively associated with pre-B ALL in clinical cases, murine models produce myeloid or T-lymphoid leukemias, which are not representative of the clinical disease. In this work, we have advanced progress towards the development an E2A-PBX1-driven experimental leukemia model. We initially determined that lineage-negative (lin-) hematopoietic progenitors expressing E2A-PBX1 expression fail to repopulate the B-lymphoid lineage when transplanted into irradiated recipient mice. Furthermore, E2A-PBX1 expressing, lin- fetal liver progenitors (FLPs) fail to differentiate into B-lymphocytes ex vivo. The majority of E2A-PBX1-expressing FLPs manifested an immature phenotype and displayed stem cell factor (SCF)-dependency and enhanced self-renewal. Additionally, these cells retained myeloid potential upon transplantation or stimulation with granulocyte macrophage colony-stimulating factor (GM-CSF). DNA binding was required for the differentiation block, suggesting that E2A-PBX1 target genes are incompatible with B-lineage specification. E2A-PBX1 FLPs had a stem cell like gene expression profile, including up-regulation of the leukemic transcription factors, Hoxa9 and Meis1. These findings explain why E2A-PBX1-driven bone marrow transplant models fail to generate B-lymphoid disease and suggest that future efforts in developing a model of E2A-PBX1-driven pre-B ALL leukemia should focus on expressing E2A-PBX1 subsequent to B-lymphoid commitment. In an attempt to override the B-lymphoid differentiation block, we next expressed E2A-PBX1 in primary pre-B cells. E2A-PBX1 induced an apoptotic response in pre-B cells, which was consistent with previous observations. Since pre-B ALL induction requires secondary genetic events, we attempted to abrogate these E2A-PBX1-mediated effects by modulating expression of the Cdkn2a locus. Loss of Cdkn2a through deletion or Bmi1 overexpression failed to ameliorate the apoptotic response, suggesting that E2A-PBX1 mediated apoptosis occurs independently of Cdkn2a in murine pre-B cells. However, in the absence of Cdkn2a, co-expression of constitutively active MerTK or Ras attenuated the E2A-PBX1 mediated apoptosis. Cumulatively, these results support the notion that t(1;19) occurs subsequent to B-lymphoid commitment and requires multiple secondary genetic lesions. Data presented in this thesis represents crucial initiating steps towards the development of a pre-B ALL model mediated by E2A-PBX1.en
dc.description.restricted-thesisThesis contains unpublished data.en
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectAcute Lymphoblastic Leukemiaen
dc.titleTowards a B-Lymphoid Model of E2A-PBX1-Mediated Leukemogenesis: Evaluating the Impact of Hematopoietic Cell of Origin on the Transformation Properties of a Leukemogenic Transcription Factoren
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