Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Timothy Ley

Abstract

The t(15;17) translocation is found in nearly 98% of acute promyelocytic leukemia: APL, FAB subtype M3) cases and results in the fusion of the promyelocytic leukemia: PML) gene with the retinoic acid receptor alpha: RARA) gene. The fusion product, PML-RARA, encodes a functionally altered transcription factor that is the initiating event in APL. To better understand the transcriptional changes associated with APL pathogenesis, we compared the gene expression profiles of APL samples to those of other acute myeloid leukemia FAB subtypes and of enriched normal human promyelocytes. We identified a signature of genes that are specifically dysregulated in APL relative to other AML subtypes and normal promyelocytes. We found that most dysregulated genes are not direct targets of PML-RARA, but are rather distal events in pathogenesis. In contrast, the APL signature was enriched in leukemia cells derived from a mouse model of APL, demonstrating that common leukemogenic pathways exist in mouse and human cells. We then observed that human APL overexpresses the Notch ligand Jagged-1: JAG1) compared to other AML and normal promyelocytes. Unlike many APL signature genes, overexpression of JAG1 is also found in human APL cell lines and in murine APL. We hypothesized that Notch signaling, which has known roles in proliferation and survival, may be important in leukemogenesis. Inhibition of Notch signaling by pharmacological and genetic approaches resulted in a loss of serial replating by marrow cells from young non-leukemic mCG-PML-RARA animals. In contrast, colony formation by wildtype marrow is unaffected by Notch inhibition, suggesting that PML-RARA expressing cells are uniquely dependent upon Notch signaling for increased self renewal. Growth of primary murine APL cells in vitro was variably reduced by pharmacological inhibition of Notch signaling: 6/9 samples), demonstrating that while Notch signaling is required for early events in leukemogenesis, in some cases it is dispensible for the fully transformed tumor. However, inhibition of Notch signaling in four tumor samples tested did not result in reduced tumor burdens in vivo. In conclusion, we have demonstrated a previously unappreciated role for the Notch signaling pathway in the development of acute promyelocytic leukemia.

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Permanent URL: http://dx.doi.org/10.7936/K7PR7T0M

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