Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


mco1147304406.pdf (1.87 MB)

ETD Abstract Container

Abstract Header

Modulation of Folate Receptor Beta for Drug Targeting in Acute Myelogenous Leukemia

Qi, Huiling
http://rave.ohiolink.edu/etdc/view?acc_num=mco1147304406

Abstract Details

2005, Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo, College of Graduate Studies.
The folate receptor (FR) type Beta, which is expressed in about 70% of acute myelogenous leukemia (AML) and can be selectively up-regulated by all-trans retinoic acid (ATRA), is a promising target for therapeutic intervention in AML. Using KG-1 and MV4-11 AML cells and recombinant 293 cells, we show that the histone deacetylase (HDAC) inhibitors Trichostatin A (TSA), valproic acid (VPA) and FK228 potentiate ATRA induction of FR-Beta. ATRA and/or TSA did not induce de novo FR synthesis in any of a variety of FR-negative cell lines tested. These results indicate that the combination of ATRA and innocuous HDAC inhibitors may be expected to facilitate selective FR-Beta-targeted therapies in AML. Mechanistic studies showed that (1) TSA did not alter the effect of ATRA on the expression of retinoic acid receptors (RARs) Alpha, Beta or Gamma, (2) ATRA increased the association of RAR Alpha with the basal FR-Beta promoter; (3) the enhancement of the ATRA effect by TSA was associated with increased acetylation of the core histones H3 and H4 at or near the basal FR-Beta promoter, (4) TSA caused a striking ATRA-dependent increase in Sp1 binding at the promoter without a further change in the association of RAR Alpha or an increase in Sp1 expression; (5) TSA further decreased the availability of putative repressor AP-1 protein(s). We further demonstrate that FR-Beta selectively mediated cell growth inhibition by the (6S) diastereoisomer of dideaza tetrahydrofolate in a manner that was potentiated by ATRA and HDAC inhibition. This study also found that ATRA induced apoptosis in MV4-11 cells but increased FR-Beta expression in the surviving cells. These surviving cells resistant to ATRA induced apoptosis can mimic the residual cells refractory to ATRA differentiation therapy. Thus this cell line can serve as a model cell line to establish FR-Beta-targeted therapy for minimal residual disease in APL. Sublines of MV4-11 cells that have uniform cell populations were isolated. Preliminary data showed that ATRA treatment increased the expression of FR-Beta in the cells collected from NOD/SCID mouse bone marrow engrafted with two such sublines demonstrating the feasibility of using this approach to develop novel FR-Beta-targeted-therapies for minimal residual disease in APL.
Manohar Ratnam, Ph.D. (Advisor)
158 p.
Biology, Molecular
Folate Receptor; Acute Myelogenous Leukemia; All-trans Retinoic Acid; Histone Deacetylase Inhibitor

Recommended Citations

Citations

  • Qi, H. (2005). Modulation of Folate Receptor Beta for Drug Targeting in Acute Myelogenous Leukemia [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1147304406

    APA Style (7th edition)

  • Qi, Huiling. Modulation of Folate Receptor Beta for Drug Targeting in Acute Myelogenous Leukemia. 2005. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1147304406.

    MLA Style (8th edition)

  • Qi, Huiling. "Modulation of Folate Receptor Beta for Drug Targeting in Acute Myelogenous Leukemia." Doctoral dissertation, University of Toledo, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=mco1147304406

    Chicago Manual of Style (17th edition)

mco1147304406
1,294
© 2005, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.