The importance of the bone marrow environment in regulating normal hematopoiesis is well established, but its contribution to myeloid leukemogenesis remains largely undefined. Cell-cell and cell-extracellular matrix interactions within the bone marrow are critical control events that constitute potential targets for leukemogenesis. The proposed aims are to explore the molecular mechanisms of stromal signalling in hematopoietic cells and the disorders of these mechanisms in acute myeloid leukemia. The expression of aminopeptidase N/CD13 (APN) on the myeloid cell surface is regulated by stromal cell contact, with the involvement of myb/ets factors. APN expression is also uniquely reduced in leukemias with the t(8;21) translocation--a lesion that generates a chimeric regulatory protein AML-ETO. The Investigator proposes that AML-ETO interferes with normal AML-1 signalling to the myb/ets-APN pathway, thus blocking APN expression. The two specific aims are designed to define the specific signals generated by the interaction of myeloid cells and stromal cells, focussing on the myb ets pathway, and to assess the impact of AML-ETO on the myb ets-APN pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA070909-03
Application #
2683657
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Shen, Grace L
Project Start
1996-04-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Mahabir, Somdat; Wei, Qingyi; Barrera, Stephanie L et al. (2008) Dietary magnesium and DNA repair capacity as risk factors for lung cancer. Carcinogenesis 29:949-56
Mahabir, S; Spitz, M R; Barrera, S L et al. (2008) Dietary boron and hormone replacement therapy as risk factors for lung cancer in women. Am J Epidemiol 167:1070-80
Mahabir, Somdat; Schendel, Kalli; Dong, Yong Quan et al. (2008) Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk. Int J Cancer 123:1173-80
Mahabir, Somdat; Forman, Michele R; Barerra, Stephanie L et al. (2007) Joint effects of dietary trace metals and DNA repair capacity in lung cancer risk. Cancer Epidemiol Biomarkers Prev 16:2756-62
Mahabir, Somdat; Spitz, Margaret R; Barrera, Stephanie L et al. (2007) Dietary zinc, copper and selenium, and risk of lung cancer. Int J Cancer 120:1108-15
Bhagwat, S V; Lahdenranta, J; Giordano, R et al. (2001) CD13/APN is activated by angiogenic signals and is essential for capillary tube formation. Blood 97:652-9
Parker, D; Rivera, M; Zor, T et al. (1999) Role of secondary structure in discrimination between constitutive and inducible activators. Mol Cell Biol 19:5601-7
Hegde, S P; Zhao, J; Ashmun, R A et al. (1999) c-Maf induces monocytic differentiation and apoptosis in bipotent myeloid progenitors. Blood 94:1578-89
Hedge, S P; Kumar, A; Kurschner, C et al. (1998) c-Maf interacts with c-Myb to regulate transcription of an early myeloid gene during differentiation. Mol Cell Biol 18:2729-37
Inoue, K; Sherr, C J; Shapiro, L H (1998) Regulation of the CD13/aminopeptidase N gene by DMP1, a transcription factor antagonized by D-type cyclins. J Biol Chem 273:29188-94

Showing the most recent 10 out of 12 publications