Preclinical evaluation of the NF-B pathway and -catenin as therapeutic targets in BCR-ABL1-induced leukemia.
BCR-ABL1 oncoprotein, resulting from t(9;22) Philadelphia chromosome translocation, is
the direct cause of chronic myeloid leukemia (CML) and is also found in some acute
B-lymphoblastic leukemia (Ph+ B-ALL) patients. While allogenic stem cell transplantation
can cure Ph+ leukemias, this procedure is risky, costly, and associated with
graft-versus-host-disease. The standard initi... read moreal therapy for CML is tyrosine kinase
inhibitors (TKIs), but they are ineffective in patients with advanced stages of CML, Ph+
B-ALL, or acquired TKI resistance. Furthermore, relapse frequently occurs after
discontinuation of TKIs, likely due to residual leukemia-initiating cells (LICs). It is
therefore important to identify signaling pathways critical to the pathogenesis of the
Ph+ leukemias, as they represent potential novel therapeutic targets for Ph+ leukemia
and to overcome resistance to TKIs. To understand the functional role of NF-κB in
BCR-ABL1-mediated myeloid and lymphoid leukemogenesis in an in vivo system, we
engineered retroviruses co-expressing BCR-ABL1 with either a super-repressor mutant form
of IκBα (IκBαSR) or kinase-inactive forms of IκB kinase
(IKKαKM or IKKβKM) to inhibit NF-κB signaling with BCR-ABL1 using
retroviral bone marrow transduction/transplantation mouse models of Ph+ leukemias. We
observed that impaired NF-κB signaling prolongs the survival of CML and B-ALL in
mice suggesting that NF-κB is activated by BCR-ABL1 in part through the canonical
IKK pathway, and validating NF-κB and IKKs as therapeutic targets for Ph+
leukemias. To interrogate the role of the nuclear, active form of β-catenin in
leukemogenesis mediated by BCR-ABL1in the development and maintenance of
leukemia-initiating cells (LICs) of CML in myeloid blast crisis, we co-expressed
constitutively active β-catenin with BCR-ABL1 using several different strategies
in the retroviral transduction/transplantation model. We found that active
β-catenin impairs both myeloid and lymphoid leukemogenesis mediated by BCR-ABL1.
These results show that the hematopoiesis defect resulting from expression of active
β-catenin in normal progenitors cannot be overcome or rescued by BCR-ABL1. In
summary, this thesis provides better understanding of the mechanistic contributions of
NF-κB and β-catenin to BCR-ABL1-mediated leukemogenesis. The data presented
herein argue for NF-κB as a potential therapeutic target in the Ph+ leukemias and
provides initial insight into the role of β-catenin in BCR-ABL1-mediated
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Richard Van Etten.
Committee: Brent Cochran, Gail Sonenshein, and Shaoguang Li.
Keyword: Physiology.read less