The overall objective of this proposal is to study the function of the normal MLL protein and of the fusion proteins formed by chromosomal translocations involving MLL that result in leukemia. They will use several approaches to identify downstream target genes of normal MLL and of two MLL fusions, MLL-AF9 and MLL-CBP. AF9 is the most common fusion partner of MLL in acute myeloid leukemia, both de novo and secondary to therapy with drugs that target DNA topoisomerase II. CBP is a fusion partner of MLL that has so far been observed only in therapy-related leukemias with one exception. They will identify target genes of normal MLL based on the ability of the MLL protein to bind to a target DNA sequence or structure using immunoprecipitation. From these experiments, they will identify targets of MLL to which it binds either directly or indirectly. They will also define the parameters that control binding, which may include DNA target sequence/structure, interacting proteins, MLL domains involved, and protein modification. Additionally, they will identify genes whose expression is altered by expression of either MLL-AF9 or MLL-CBP fusion proteins using transient or inducible stable expression systems followed by gene expression pattern analysis on a genome-wide scale using cDNA microarrays and oligonucleotide microarray chips. This will identify targets whose altered expression may be important in leukemogenesis, regardless of the mechanism. The direct and the downstream targets will help identify cellular pathways that are deregulated by the fusion proteins and that may be critical for the ultimate leukemia phenotype. Together, the experiments proposed in these two specific aims will provide valuable information regarding the mechanism of MLL and MLL-partner gene function in normal and in leukemic cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA078438-05
Application #
6376833
Study Section
Pathology B Study Section (PTHB)
Project Start
1998-08-10
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$110,484
Indirect Cost
Name
Loyola University Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Xia, Zhen-Biao; Popovic, Relja; Chen, Jing et al. (2005) The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression. Proc Natl Acad Sci U S A 102:14028-33
Chinwalla, Vandana; Chien, Andy; Odero, Maria et al. (2003) A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15. Oncogene 22:1400-10
Kuefer, Martin U; Chinwalla, Vandana; Zeleznik-Le, Nancy J et al. (2003) Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14). Oncogene 22:1418-24
Xia, Zhen-Biao; Anderson, Melanie; Diaz, Manuel O et al. (2003) MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc Natl Acad Sci U S A 100:8342-7
Baron, Beverly W; Anastasi, John; Thirman, Michael J et al. (2002) The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: implications for a role of BCL6 in the down-regulation of apoptosis. Proc Natl Acad Sci U S A 99:2860-5