All ETDs from UAB

Advisory Committee Chair

Christopher A Klug

Advisory Committee Members

Louis B Justement

Janusz H Kabarowski

Richard D Lopez

Thomas M Ryan

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The t(8;21) translocation, which generates an AML1-ETO fusion protein (also known as RUNX1-ETO), is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Murine studies have demonstrated that AML1-ETO promotes the accumulation of myeloid progenitor cells with self-renewal capability and impaired differentiation capacity. However, AML1-ETO+ mice do not progress to AML in the absence of additional mutations, suggesting that expression of the translocation is insufficient for leukemogenesis. This hypothesis is supported by studies demonstrating the persistence of AML1-ETO-expressing hematopoietic progenitors obtained from patients in long-term clinical remission. Mutations affecting receptor tyrosine kinases, particularly c-KIT, are commonly detected in t(8;21)+ AML. In AML1-ETO+ patient samples, differing classes of activating c-KIT mutations have been observed with varying prevalence. The most common (12-48%) involves mutations that occur in the activation loop of the phosphotransferase domain, like D814V, while another involves deletions within exon 8, a region mediating receptor dimerization (2-13% of cases). To formally investigate whether distinct activating c-Kit mutations differ in their capacity to drive AML1-ETO-associated AML, we used a retroviral transduction strategy to co-express AML1-ETO with c-KitD814V or a representative exon 8 mutant (c-KitT417Iδ418-419) in murine bone marrow progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted mice showed that AML1-ETO;c-KitD814V co-expression resulted in three non-overlapping phenotypes. In 45% of animals, an AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative neoplasm (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, AML1-ETO;c-KitT417Iδ418-419 co-expression promoted exclusively AML in a fraction (51%) of reconstituted mice with a median latency nearly double that observed in AML1-ETO;c-KitD814V mice that developed AML. Analysis of clonality indicated that acquisition of oncogenic events in addition to AML1-ETO and an activated c-Kit receptor were necessary for transformation in all cases. The neoplastic phenotype differences between AML1-ETO;c-KitD814V and AML1-ETO;c-KitT417Iδ418-419 mice indicate that distinct activating c-Kit mutants differ in leukemogenic potential, which could account for the disparity in prevalence of each c-KIT mutation concurrent with AML1-ETO in human AML.

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