All ETDs from UAB

Advisory Committee Chair

Christopher A Klug

Advisory Committee Members

Etty Benveniste

Louis B Justement

Janusz H Kabarowski

Richard D Lopez

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Acute myeloid leukemia (AML) comprises approximately 25% of newly diagnosed cases of leukemia each year. The constitutive activation of the classical NF-κB signaling pathway has been observed in up to 70% of AML cases, and could be due to mutations upstream involving the PI3K-Akt cascade, which is also constitutively active in a majority of cases. In mice, constitutive activation of Akt either through deletion of the negative regulator of PI3K-Akt, PTEN, or by expression of Myr-Akt induces rapid stem cell loss along with a lethal, transplantable myeloproliferative disorder and AML. These studies show that constitutive Akt and NF-κB signaling distinguish leukemia-initiating cells from normal hematopoietic stem cells (HSC). Although constitutive activation of NF-κB is observed in AML, it is unknown whether NF-κB signaling alone is sufficient to promote leukemogenesis and to what extent NF-κB signaling plays a role in HSC biology. This study used retroviral overexpression of activated IKKß (IKKßSS/EE) to induce constitutive classical NF-κB signaling and an inducible conditional knockout mouse model (Mx1-Cre;NemoF/F) to efficiently repress classical NF-κB signaling to address these questions. Activation of NF-κB induced a loss of HSC over 10 weeks likely due to a loss of self-renewal potential because an increase in apoptosis or HSC mobilization to the spleen was not observed. Persistent NF-κB activation also promoted differentiation and a transient increase in monocytes at the expense of B-cell lymphopoiesis. In comparison to activated Akt phenotypes, constitutive NF-κB signaling did not induce progression to MPD or AML. Conversely, repression of NF-κB resulted in the loss of one of the earliest non-self-renewing MPP subsets, whereas the stem cell compartment was unaffected, likely due to either a block in differentiation or an increase in apoptosis, which was observed systemically. Overall, these results show that constitutive NF-κB signaling is not sufficient to initiate AML, and that other genetic changes likely occur prior to activation of constitutive NF-κB signaling. In addition, the repression of NF-κB suggests a fundamental requirement for NF-κB in the survival and maintenance of MPPs.

Share

COinS