Preclinical evaluation of the NF-B pathway and -catenin as therapeutic targets in BCR-ABL1-induced leukemia.
Hsieh, Mo-Ying.
2011
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Abstract: The 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 initial th... read moreerapy 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-B 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 IB (IBSR) or kinase-inactive forms of IB kinase (IKKKM or IKKKM) to inhibit NF-B signaling with BCR-ABL1 using retroviral bone marrow transduction/transplantation mouse models of Ph+ leukemias. We observed that impaired NF-B signaling prolongs the survival of CML and B-ALL in mice suggesting that NF-B is activated by BCR-ABL1 in part through the canonical IKK pathway, and validating NF-B and IKKs as therapeutic targets for Ph+ leukemias. To interrogate the role of the nuclear, active form of -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 -catenin with BCR-ABL1 using several different strategies in the retroviral transduction/transplantation model. We found that active -catenin impairs both myeloid and lymphoid leukemogenesis mediated by BCR-ABL1. These results show that the hematopoiesis defect resulting from expression of active -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-B and -catenin to BCR-ABL1-mediated leukemogenesis. The data presented herein argue for NF-B as a potential therapeutic target in the Ph+ leukemias and provides initial insight into the role of -catenin in BCR-ABL1-mediated leukemogenesis.
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 - ID:
- jq085x76w
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