This application is for renewal of our NCI-funded R01 grant entitled: "Functional Characterization of MLL Gene Fusions" (last score:17.2 percentile). The central hypothesis of our work is that the MLL Partial Tandem Duplication (PTD) represents a primary molecular defect in myeloid hematopoeitic progenitor cells that is responsible, at least in part, for leukemic transformation, and will prove to be a valuable target for therapeutic intervention in MLL PTD acute myeloid leukemia (AML) patients who have a poor prognosis. Our overall goal is to elucidate molecular mechanisms underlying this subset of AML such that we will have the greatest impact on increasing cure rate of this disease by molecular-based risk stratification and targeted therapeutics. During the previous funding period, our early success in generating the heterozygous Mll ptd knock-in mouse allowed us to begin our efforts 1) examining hematopoiesis and downstream Mll targets in vitro and in vivo- we found proliferative and self-renewal abnormalities in hematopoietic progenitors but no frank leukemia;2) characterizing the first overt phenotype observed- skeletal deformities associated with aberrant HoxA gene expression and 3) elucidating the novel epigenetic mechanism responsible for HoxA gene deregulation in Mllptd/wt mice. We also carried out genome-wide profiling in human MLL PTD AML and have gained considerable insight into MLL PTD-associated pathways. Indeed, we demonstrated primary MLL PTD AML blasts express the MLL self-fusion but silence the MLL wild-type allele. The latter can be reversed by pharmacological inhibitors of DNA methyltransferase and histone deacetylase and also by direct targeting of the MLL PTD using anti-sense oligodeoxynucleotides. Both approaches resulted in enhanced apoptosis of these leukemic blasts in vitro. During the next funding cycle, we will extend these findings through the following aims: 1) further characterize the Mll ptd to best understand how this mutation impacts the genesis and propagation of AML;2) elucidate cooperating events that together with the Mll ptd give rise to AML. Indeed, we recently generated a Mll ptd/Flt3 itd double mutant mouse model, and 100% of these mice develop aggressive acute leukemia. Initial full phenotypic analyses in two mice reveal AML or undifferentiated stem cell acute leukemia. These mice will be used to carry out hypothesis-driven research as outlined and will be useful for assessing novel targeted therapeutics. Collectively, we believe this work will reveal insights as to how to best treat MLL PTD AML patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089341-09
Application #
8196825
Study Section
Special Emphasis Panel (ZRG1-ONC-S (04))
Program Officer
Howcroft, Thomas K
Project Start
2000-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$278,052
Indirect Cost
$92,684
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mishra, Anjali; Sullivan, Laura; Caligiuri, Michael A (2014) Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res 20:2044-50
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Bernot, Kelsie M; Nemer, John S; Santhanam, Ramasamy et al. (2013) Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches for human disease. Blood 122:3778-83
Park, Il-Kyoo; Mishra, Anjali; Chandler, Jason et al. (2013) Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood 121:2064-73
Whitman, Susan P; Maharry, Kati; Radmacher, Michael D et al. (2010) FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 116:3622-6
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Whitman, Susan P; Ruppert, Amy S; Radmacher, Michael D et al. (2008) FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood 111:1552-9

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