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Novel mechanisms of transcriptional regulation by leukemia fusion proteins

Gow, Chien-Hung, M.D.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1394724980

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Transcription factors and chromatin structure are master regulators of homeostasis during hematopoiesis. Regulatory genes for each stage of hematopoiesis are activated or silenced in a precise, finely tuned manner. Many leukemia fusion proteins are produced by chromosomal translocations that interrupt important transcription factors and disrupt these regulatory processes. Leukemia fusion proteins E2A-Pbx1 and AML1-ETO involve normal function transcription factor E2A, resulting in two distinct types of leukemia: E2A-Pbx1 t(1;19) acute lymphoblastic leukemia (ALL) and AML1-ETO t(8;21) acute myeloid leukemia (AML). E2A, a member of the E-protein family of transcription factors, is a key regulator in hematopoiesis that recruits coactivators or corepressors in a mutually exclusive fashion to regulate its direct target genes. In t(1;19) ALL, the E2A portion of E2A-Pbx1 mediates a robust transcriptional activation; however, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) AML and ETO-2 in hematopoietic cells. It is unclear how this context-dependent regulation of E2A-dependent transcription allows E2A protein to regulate transcription in response to variable intracellular levels of corepressor. In this study, we discovered that unlike HEB, another E-protein, the activation domain 1 (AD1) of E2A is inhibited for corepressor interaction by E2A-specific amino acid changes in the p300/CBP and ETO target motif, which interacts with only one of these targets at a time. At physiological levels of corepressor, E2A-Pbx1 escapes endogenous ETO-2 binding to confer its oncogenic ability via AD1 and AD2 cooperative activity to facilitate coactivator recruitment. In the presence of aberrantly high levels of AML1-ETO, E2A interacts with the corepressor to silence expression of E-protein target genes. This process requires the downstream ETO-interacting sequence (DES) domain of E2A to compensate for the weak binding between E2A-AD1 and AML1-ETO. This novel E2A-specific cofactor exchange mechanism provides an explanation for the specific E2A determinants that oppositely link corepressor function to distinct leukemogenic pathways. In the second part of this study, we explored the regulatory mechanism of histone deacetylase 3 (HDAC3), which mediates chromatin structural dynamics to control transcription. In E-protein-mediated transcription, corepressor AML1-ETO/ETO associates with HDAC3 by recruiting nuclear receptor corepressors N-CoR/SMRT to packed chromatin, thus repressing transcription. Functional HDAC3 must form a stable complex with N-CoR or SMRT, which individually and independently bind to HDAC3. We identified a novel cell-independent HDAC3 regulatory mechanism, which is significant for its reduced protein levels of corepressor (N-CoR or SMRT) and accelerates HDAC3 clearance to prevent complex formation between HDAC3 and its other corepressor. We also demonstrated the formation of an HDAC3-corepressor complex via a stepwise procedure in which the unique C-terminus of HDAC3 is critical for the assembly process. These findings may be useful in efforts to reverse the leukemogenic phenotypes and in the development of new treatments for leukemia.
Sohaib Khan, Ph.D. (Committee Chair)
Song-Tao Liu, Ph.D. (Committee Member)
Robert Brackenbury, Ph.D. (Committee Member)
Peter Stambrook, Ph.D. (Committee Member)
Jinsong Zhang, Ph.D. (Committee Member)
228 p.
Oncology
transcriptional regulation; leukemia fusion protein; E-protein; E2A-Pbx1; AML1-ETO; HDAC3

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Citations

  • Gow, M.D., C.-H. (2014). Novel mechanisms of transcriptional regulation by leukemia fusion proteins [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1394724980

    APA Style (7th edition)

  • Gow, M.D., Chien-Hung. Novel mechanisms of transcriptional regulation by leukemia fusion proteins. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1394724980.

    MLA Style (8th edition)

  • Gow, M.D., Chien-Hung. "Novel mechanisms of transcriptional regulation by leukemia fusion proteins." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1394724980

    Chicago Manual of Style (17th edition)

ucin1394724980
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© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.