Advisor(s)
Christopher Klug
Committee Member(s)
Xinbin Chen
Peter Emmanuel
Michael Ruppert
Tim Townes
Document Type
Dissertation
Date of Award
2007
Abstract
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.
ProQuest Publication Number
ISBN
978-0-549-46753-3
Recommended Citation
Ko, Rose Marie, "The Effect Of The Aml1-Eto Translocation On Cell Cycle Tumor Suppressor Gene Function" (2007). All ETDs from UAB. 3734.
https://digitalcommons.library.uab.edu/etd-collection/3734
