All ETDs from UAB

Advisory Committee Chair

Christopher Klug

Advisory Committee Members

Xinbin Chen

Peter Emmanuel

Michael Ruppert

Tim Townes

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The t(8;21)(q22;q22) AML1-ETO translocation is one of the most frequent translocations in acute myeloid leukemia (AML), occurring in approximately 12% of cases. Our laboratory has generated a mouse model in which AML1-ETO is expressed in hematopoietic progenitor cells using a retroviral vector and assayed using bone marrow transplantation. Animals transplanted with AML1-ETO-expressing cells failed to develop leukemia. However, AML1-ETO promoted significant expansion of immature myeloid cells suggesting a “pre-leukemic” state that requires secondary mutations for disease progression. In addition, analysis of cell cycle kinetics in AML1-ETOexpressing myeloid progenitor cells showed that AML1- ETO slowed G1 to S phase progression compared to control animals. Further analysis using quantitative RT-PCR showed that AML1-ETO increased expression of p15Ink4b and p16Ink4a, which may account for the inhibition of the G1 to S phase transition. Interestingly, p15INK4b is a tumor suppressor that is inactivated by hypermethylation in over 70% of human AML patient samples. In addition, p16INK4a is frequently inactivated in the FAB-M2 subset of AML that expresses the t(8;21). These observations suggest that loss of p15Ink4b or p16Ink4a may cooperate with AML1-ETO in disease progression. To test this hypothesis, p15Ink4b-/-, p16Ink4a-/-, or wild-type bone marrow cells were transduced with AML1- ETO or control retroviruses and then transplanted into lethally irradiated recipient animals. Analysis of reconstituted animals at two months post-transplant showed that iii p15Ink4b or p16Ink4a deficiency did not accelerate disease progression in the presence of AML1-ETO. However, loss of p15Ink4b alone did cause a modest expansion of hematopoietic stem cells and a 2-fold increase in myeloid progenitor cells based in FACS analysis and differential bone marrow cell counts. These data suggest that the loss of either p15Ink4b or p16Ink4a alone is not a major contributing factor to pathogenesis associated with the AML1-ETO translocation.



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