The role of NF-κB in BCR-ABL-driven oncogenic transformation and in hematopoiesis Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 22, 2019
  • Stein, Sarah
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Chronic myeloid leukemia is a malignant clonal disorder of hematopoietic stem cells that results in increased and deregulated growth of myeloid cells. About 95% of CML cases arise from the formation of the Philadelphia (Ph) chromosome, resulting in the expression of BCR-ABL, an oncoprotein with constitutive tyrosine kinase activity that drives oncogenesis. Current therapeutics for CML includes the BCR-ABL inhibitor, imatinib, which results in molecular remission in only 4% of patients. Drug resistance also occurs in CML through point mutations in BCR-ABL itself, or through the upregulation of secondary signaling pathways. Therefore, insight into novel therapeutic targets is needed for the treatment of CML. Previous work has shown that BCR-ABL expression induces the activation of a dimeric transcription factor, NF-κB and that its activity is required for efficient cellular transformation by BCR-ABL. Here, we show that BCR-ABL utilizes NF-κB for survival of transformed cells, and for transformation to initiate to disease in vivo. Due to the role of NF-κB activity in the development and function of numerous hematopoietic cell types, we also investigate the role of classical NF-κB subunit, p65, in normal hematopoiesis. Results indicate that the loss of p65 in the hematopoietic compartment leads to defects in hematopoiesis due to loss of hematopoietic stem cell homeostasis and the activation of alternative signaling pathways. Together, these data show that p65 is an important regulator of hematopoiesis. These data indicate that therapeutics involving the inhibition of NF-κB, although promising for the treatment of CML, should be used with caution.
Date of publication
Resource type
Rights statement
  • In Copyright
  • Baldwin, Albert
  • Doctor of Philosophy
Graduation year
  • 2012

This work has no parents.