In acute myeloid (AML) and lymphoid (ALL) leukemias, the MLL gene fuses with over 50 partner genes or can be rearranged as the result of a self-fusion creating the partial tandem duplication {MLL-PJD). We discovered the MLL-PTD and have investigated the MLL-PTD role in leukemogenesis and its prognostic impact. We were the first to report that MLL-PTD occurs more frequently in cytogenetically normal (CN)- AML and in AML with +11 and was associated with adverse prognosis. Although more recently we have shown that the outcome of MLL-PTD AML patients has improved with intensive treatment, most of them die of their disease, thereby underscoring the need for novel and more """"""""personalized"""""""" treatment approaches. Interestingly, we observed MLL-PTD blasts from patients with dismal outcome often harbor additional adverse prognostic molecular markers, such as the FLT3 internal tandem duplication {FLT3 ITD) and that certain epigenetic aberrations are characteristically associated with the MLL-PTD. These data, therefore suggest that additional genetic and epigenetic """"""""hits"""""""" are necessary for development of the MLL- PTD leukemia phenotype. In support of the """"""""multiple hits"""""""" leukemogenic model, the Mil PTD as a single knocked-in defect in mice benignly alters hematopoiesis but does not induce leukemia, while it cooperates with the knocked-in Flt3 ITD defect to induce fatal AML. Reversion of epigenetic changes by hypomethylating agents and histone deacetylase inhibitors increases sensitivity of MLL PTD cells to chemotherapy. Based on these findings, therefore, we hypothesize that MLL PTD AML can be used as a model to elucidate the molecular mechanism(s) leading to multi-step leukemogenesis so that novel targeting therapies can be developed. To test our hypotheses, we collectively as a laboratory and clinical investigational team working together propose the following three aims: 1. To further characterize genetic and epigenetic mechanisms leading to MLL PTD AML using an Mil PTD/Flt3 ITD murine model;2. To design novel therapeutic approaches targeting genetic and epigenetic aberrations in MLL PTD AML;3. To perform an expanded Phase I clinical trial using a combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors followed by intensive chemotherapy to assess safety and efficacy in adult patients with relapsed or refractory AML, particularly in patients with the MLL PTD. Our ultimate goal is to improve outcome of MLL PTD AML patients. We anticipate, however, that some of the discoveries derived from this project will also improve our understanding and our ability to treat other subtypes of AML.

Public Health Relevance

We were the first to identify a type of acute myeloid leukemia (AML) characterized by a gene mutation called MLL PTD that is associated with short survival. We have created a mouse model of MLL PTD leukemia. We will use this model to understand the mechanisms through which MLL PTD causes leukemia and test novel therapies. Our laboratory discoveries will be rapidly moved to the clinic. Our goal is to improve the outcome of patients with MLL PTD AML, but also to extend our discoveries from to other subtypes of AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA140158-01
Application #
7715172
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M1))
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$278,237
Indirect Cost
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mims, Alice S; Mishra, Anjali; Orwick, Shelley et al. (2018) A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica 103:982-987
Walker, Christopher J; Oakes, Christopher C; Genutis, Luke K et al. (2018) Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA. Leukemia :
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies. Leukemia 32:1338-1348
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2018) NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia 32:2536-2545
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Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505
Papaioannou, Dimitrios; Nicolet, Deedra; Volinia, Stefano et al. (2017) Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia. Haematologica 102:1391-1400
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218
Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285
Walker, C J; Eisfeld, A-K; Genutis, L K et al. (2017) No evidence for microsatellite instability in acute myeloid leukemia. Leukemia 31:1474-1476

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