The function of the HoxA9 transcription factor is of critical interest in human acute myeloid leukemia (AML) since oncogenic activation of HoxA9 is induced by multiple chromosomal translocations;however, independent studies indicate that the expression level of HoxA9 is prognostic in human AML lacking these chromosomal abnormalities. Thus, an understanding of HoxA9 signaling would significantly impact patients with AML. Importantly, the direct transcriptional targets of HoxA9 and thus mechanism of HoxA9-mediated transformation remain largely unknown. The Growth factor independent-1 (Gfi1) transcriptional repressor is known to induce granulopoiesis, inhibits myeloid progenitor proliferation, and is mutated in patients with severe congenital neutropenia (SCN). SCN patients are at increased risk for AML. We have recently shown that 1) Gfi1 represses HoxA9, Meis1 and Pbx1 expression, 2) Gfi1 and HoxA9 demonstrate dramatic epistatic relationships, and 3) Gfi1 loss of function is potently preleukemic. The antagonism between Gfi1 and HoxA9 is conserved to Drosophila, and our preliminary data indicate that in mammalian myeloid progenitors centers upon the expression of microRNA encoding genes. We hypothesize that these microRNA mediate Hox-based leukemic signaling, and that specific microRNA inhibitors abort the maintenance of Hox-based leukemia initiating cells. The proposed research will delineate the functional role of microRNA as molecular signaling effectors/clients of Hox-based leukemia oncoproteins.

Public Health Relevance

Acute myeloid leukemia, a cancer of the blood, accounts for 1.2% of cancer deaths in the United States;however, rates are expected to increase as the population ages and successful therapeutics are expected to benefit patients with leukemia and abnormal hematopoiesis. The proposed work may be considered both an examination of oncogenic signaling, and a pre-clinical proof of principle for the use of microRNA inhibitors in the treatment of leukemia. microRNA antagonists are being developed for clinical use by several companies and the proposed experiments are anticipated to be pioneering work to move the concept forward.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159845-03
Application #
8472461
Study Section
Special Emphasis Panel (ZRG1-OBT-S (02))
Program Officer
Mufson, R Allan
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$298,427
Indirect Cost
$103,377
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Raines, Anna M; Adam, Mike; Magella, Bliss et al. (2013) Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts. Development 140:2942-52
Phelan, James D; Saba, Ingrid; Zeng, Hui et al. (2013) Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genet 9:e1003713
Khandanpour, Cyrus; Phelan, James D; Vassen, Lothar et al. (2013) Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell 23:200-14