Studies in mice and humans suggest major HOX genes may integrate myelodysplastic and leukemogenic activities of several different oncogenic proteins and molecular pathways in high risk human myelodysplastic syndrome (MDS) and promote its progression to acute myeloid leukemia {AML). Studies summarized in this proposal suggest that upregulation of HOXA9 elicits a transforming pathway in pluripotent bone marrow stem cells, leading initially to trilineage dysplasia and chromosomal instability and culminating in high risk AML with complex karyotypes and very poor outcomes regardless of therapy. It has not been possible to delineate molecular pathways downstream of HOXA9, impeding efforts to identify key proteins that could be specific targets for the design of small molecule inhibitors for treatment of MDS and prevention of progression to AML. Transcription factors like HOXA9 have not been proven to be targets for inhibition by small molecules, so delineation of crucial downstream pathways is critical for the design of targeted therapies. The new opportunity to be exploited in this project is development of small inhibitory RNA (siRNA) strategies to """"""""knock-down"""""""" HOXA9 levels in human AML cell lines, so cell biologic consequences of down-regulating crucial HOXA9-mediated pathways can be defined. Preliminary data attest to our ability to """"""""knock-down"""""""" HOXA9 levels to less than 10% of preexisting levels in human AML cell lines. We also show that down-regulation of HOXA9 markedly retards growth of these cells, suggesting an effect of HOXA9 in maintaining proliferative capacity of altered stem cells that give rise to MDS and eventually contribute to leukemic transformation, after accumulation of additional genetic abnormalities. Our fundamental hypothesis is that we will identify downstream targets within the HOXA9 pathway that contribute to disordered hematopoietic cell development in MDS and leukemic transformation to AML, including those that function as enzymes and can be advantageously inhibited by small molecules. The identification of these targets will be addressed by a combination of gene expression analysis using microarrays and chromatin immunoprecipitation techniques. The significance of HOXA9 targets will be validated by """"""""knocking-down"""""""" protein levels with siRNA and assessing whether function inhibition also retards aberrant cell growth in a myeloid cell line model system. A positive result would provide proof-of-principle that such proteins are suitable targets for available drugs or the development of small molecule inhibitors that could be rapidly tested in Project 1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA108631-03
Application #
7726935
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$292,680
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Sievers, Quinlan L; Petzold, Georg; Bunker, Richard D et al. (2018) Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362:
Fink, Emma C; McConkey, Marie; Adams, Dylan N et al. (2018) CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood 132:1535-1544
Kahn, Josephine D; Miller, Peter G; Silver, Alexander J et al. (2018) PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095-1105
Tothova, Zuzana; Krill-Burger, John M; Popova, Katerina D et al. (2017) Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell 21:547-555.e8
Ajore, Ram; Raiser, David; McConkey, Marie et al. (2017) Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol Med 9:498-507
Yamazaki, Jumpei; Jelinek, Jaroslav; Lu, Yue et al. (2015) TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor-Binding Sites in Chronic Myelomonocytic Leukemia. Cancer Res 75:2833-43
Malouf, Gabriel G; Zhang, Jianping; Yuan, Ying et al. (2015) Characterization of long non-coding RNA transcriptome in clear-cell renal cell carcinoma by next-generation deep sequencing. Mol Oncol 9:32-43
Fink, Emma C; Ebert, Benjamin L (2015) The novel mechanism of lenalidomide activity. Blood 126:2366-9
Lindsley, R Coleman; Mar, Brenton G; Mazzola, Emanuele et al. (2015) Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125:1367-76
Guirguis, Andrew A; Ebert, Benjamin L (2015) Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. Curr Opin Cell Biol 37:61-7

Showing the most recent 10 out of 80 publications