Rearrangements of the ALL-1/MLL1 gene, resulting in production of ALL-1 fusion proteins, underlie the vast majority of infant acute leukemias and of a substantial part of a therapy-related leukemia. The way by which the fusion proteins trigger leukemia is not known. Here we attack this issue in several directions: 1) we have recently found that expression of ALL-1 fusion proteins in leukemic and transfected cells results in upregulation of a specific micro RNA. miR-191. We found that the upregulation is due to recruitment of ALL-1 fusion proteins, together with the general processor of microRNAs-Drosha, to the miR-191 locus. Since Drosha is not recruited with normal ALL-1 to the same locus (nor was it shown to be bound to other rniR loci), we consider this recruitment as very significant in miR-191 upregulation. Included in the proposal are experiments concerning potential association between ALL-1 fusion proteins and Drosha, involvement of Drosha's recruitment in miR-191 overexpression in solid tumors, direct role of miR-191 in onset of acute leukemia, effect of miR-191 overexpression on differentiation of hematopoietic precursor cells, and identification of miR-191 target gene(s). 2) We have used a combination of conventional columnes, immunearflnlty purification, and mass spectrometry analysis to identify a series of proteins associated with ALL-1/AF4 within a multiprotein complex. The identified proteins will be examined by multiple approaches to determine whether they constitute integral components of the ALL-1/AF4 complex. A follow-up will focus on interesting components. 3) Following our success in bringing off a genome-wide location analysis of normal ALL-1, we will extend it to a global analysis of the gene targets of ALL-1 fusion proteins ALL-1/AF4 and ALLVAF9 in leukemic lymphoid and myeloid cell lines, respectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128609-05
Application #
7884279
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mufson, R Allan
Project Start
2006-09-27
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$313,613
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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