Myeloid translocation Gene 16 as a determinant of notch-driven Leukemic Phenotype

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Title Myeloid translocation Gene 16 as a determinant of notch-driven Leukemic Phenotype
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Lucente, Helena Elizabeth
Date 2018
Description Notch expression is necessary for hematopoietic cell fate determination during fetal development and for proper differentiation of T-cells. As Notch signaling is essential for hematopoiesis, its misregulation can promote hematopoietic malignancies. Activated Notch has been found in lymphoid leukemias and lymphomas, while Notch pathway inactivation has been associated with myeloid leukemias. Myeloid Translocation Gene (MTG)-16 interacts directly with the intracellular domain of Notch (N-ICD) and is required for in vitro T-cell fate specification. In in vitro assays, double positive T-cell development can be restored in Mtg16 -/- progenitors by enforced expression of MTG16, but not an MTG16 derivative which lacks N-ICD binding site (MTG16-Δ2N) and mimics a naturally occurring MTG16 splice variant (MTG16C). This finding suggests that MTG16 is one determinant of context-dependent, Notch-driven cell fate in hematopoiesis. To assess the impact of the N1-ICD-MTG16 interaction as a determinant of the malignant phenotype, we infected Mtg16 -/- bone marrow with retroviral bicistronic constructs that express either N1-ICD alone, N1-ICD with MTG16, or N1-ICD with MTG16-Δ2N and transplanted bone marrow into lethally irradiated recipients. We found that mice transplanted with Mtg16 -/- progenitors transduced with N1-ICD or N1-ICD along with MTG16 and transplanted into syngenic recipients develop T- cell leukemia, but recipients of N1-ICD co-expressed with MTG16-Δ2N develop T-cell/myeloid bilineal mixed-phenotype acute leukemia (MPAL). Analysis of gene expression in blasts from N1-ICD:2A:MTG16-Δ2N leukemias showed repression of Notch target genes when compared to leukemias arising from N1-ICD expression alone. Notably, MTG16-Δ2N retains the ability to bind the N1-ICD transcriptional partner CSL and to repress Notch target genes as an element of a CSL-dependent transcriptional repressor complex. These findings suggest that MTG16-Δ2N, and perhaps MTG16C, retain repressor functions at Notch target genes in the context of N1-ICD expression and enable an MPAL phenotype characterized by distinct populations of blasts with T-cell and myeloid features.
Type Text
Publisher University of Utah
Subject Molecular biology; Leukemia; Genotype & phenotype
Dissertation Name Doctor of Philosophy
Language eng
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s6673gcn
Setname ir_etd
ID 1525831
Reference URL https://collections.lib.utah.edu/ark:/87278/s6673gcn
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