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.

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National Cancer Institute (NCI)
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Ohio State University
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Niederwieser, C; Kohlschmidt, J; Volinia, S et al. (2015) Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia. Leukemia 29:567-75
Mani, R; Mao, Y; Frissora, F W et al. (2015) Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia. Leukemia 29:346-55
Zhong, Y; El-Gamal, D; Dubovsky, J A et al. (2014) Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia 28:1158-63
Marcucci, Guido; Yan, Pearlly; Maharry, Kati et al. (2014) Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score. J Clin Oncol 32:548-56
Eisfeld, Ann-Kathrin; Schwind, Sebastian; Patel, Ravi et al. (2014) Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway. Sci Signal 7:ra36
Becker, H; Maharry, K; Mrózek, K et al. (2014) Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8. Leukemia 28:1754-8
Alachkar, Houda; Santhanam, Ramasamy; Maharry, Kati et al. (2014) SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome. J Clin Invest 124:1512-24
Wang, David J; Ratnam, Nivedita M; Byrd, John C et al. (2014) NF-?B functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells. Cell Rep 9:90-103
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Pan, Li; Woodard, John L; Lucas, David M et al. (2014) Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. Nat Prod Rep 31:924-39

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