Acute leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1). More than 40 different MLL translocations have been reported, but the t(4;11) (MLL-AF4) is particularly common in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 leukemias have a poor prognosis. This is particularly true for infant leukemia where approximately 80% of cases will harbor rearrangement of the MLL gene. We have recently developed a conditional mouse model of Mll-AF4 ALL that recapitulates the gene expression profiles and histone methylation profiles of human MLL-AF4 ALL. Experiments described in this proposal will build upon these previous studies and characterize leukemia development with a particular focus on histone methylation. We will determine which cell types are permissive for Mll-AF4 leukemia development including hematopoietic stem cells (HSC) and early lymphoid committed cells. We will also determine if MLL-AF4 leukemia cell survival is dependent upon the histone methyltransferase Dot1L. These studies will provide a highly detailed characterization of the cells of origin of Mll-AF4 ALL, and begin to determine if histone methyltransferases are potential therapeutic targets in this disease.

Public Health Relevance

The MLL-AF4 translocation is found in acute lymphoblastic leukemias that confer a poor prognosis. We will use sophisticated mouse models and human leukemia cells, to characterize the abberant molecuar and cellular processes that are induded during leukemia development, and determine if inhibition of specific histone methyltransferases could be a therapeutic target in this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA140575-01A1
Application #
7886077
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2010-03-01
Project End
2015-01-31
Budget Start
2010-03-01
Budget End
2011-01-31
Support Year
1
Fiscal Year
2010
Total Cost
$355,690
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Kühn, Michael W M; Hadler, Michael J; Daigle, Scott R et al. (2015) MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica 100:e190-3

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