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 hematopoietic 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 an 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.
Collectively, we believe this work will reveal insights as to how to best treat patients with Acute Myelogenous Leukemia and the Partial Tandem Duplication of the Mixed Lineage Leukemia Gene.
|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|
|Mundy-Bosse, Bethany L; Scoville, Steven D; Chen, Li et al. (2016) MicroRNA-29b mediates altered innate immune development in acute leukemia. J Clin Invest 126:4404-4416|
|Park, I-K; Mundy-Bosse, B; Whitman, S P et al. (2015) Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia 29:2382-9|
|Wang, Yin; Liu, Yan; Tang, Fei et al. (2014) Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells. Blood 124:1127-35|
|Mishra, Anjali; Sullivan, Laura; Caligiuri, Michael A (2014) Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res 20:2044-50|
|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|
|Bernot, K M; Siebenaler, R F; Whitman, S P et al. (2013) Toward personalized therapy in AML: in vivo benefit of targeting aberrant epigenetics in MLL-PTD-associated AML. Leukemia 27:2379-82|
|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|
|Zorko, Nicholas A; Bernot, Kelsie M; Whitman, Susan P et al. (2012) Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias. Blood 120:1130-6|
|Zhang, Yue; Yan, Xiaomei; Sashida, Goro et al. (2012) Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells. Blood 120:1118-29|
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