AML is a blood cancer that arises from the uncontrolled expansion of immature white blood cells. AML patients display an extraordinarily high rate of mortality, with only 23% surviving beyond 5 years. This poor prognosis results from both a high incidence of leukemia relapse and the ineffectiveness and toxicity of current therapies. While these alarming realities demand the development of more effective AML chemotherapies, this notion is complicated by two major factors. First, a small but distinct fraction of leukemia cells (called leukemia-initiating cells or LICs) are able to evade conventional drugs and cause leukemia relapse. Second, AML has many different sub-types, each with different genetic abnormalities that limit the ability to design broad-spectrum anti- AML drugs. Therefore, identifying and targeting common molecular irregularities specifically found in LICs is a critical basis for developing successful broad-based AML therapies. Using a gene expression dataset derived from a large human AML sample set, we have identified that the FOXO family of genes are inappropriately activated in ~40% of AML cases. Using a mouse model of AML we also found that FOXOs are critical regulators of LICs. Further investigation revealed that approximately 60% of the leukemic samples were resistant to FOXO suppression. Those cells that were FOXO insensitive had abnormalities of another pathway, the JNK gene family. Inhibition of both FOXO and JNK, using drugs to inhibit JNK enzymes, resulted in marked killing of even the resistant cancer cells. We now aim to determine the downstream effectors of the FOXO and JNK pathways that allow these genes to promote leukemogenesis. Specifically, we will examine how the activities of the oncogenes c-JUN and ?- catenin are affected by manipulation of the FOXO and JNK pathways. Further, we want to evaluate whether pharmacological exploitation of these pathways provides a proof-in-principal strategy for the treatment of AML. We will accomplish this by evaluating how the combined inhibition of FOXO and JNK signaling impacts human AML cell growth and LIC function. We believe that these proposed experiments align perfectly with the National Cancer Institute's mission to uncover new molecular signatures in human cancer that could improve diagnostic tools and provide platforms for the design of new, more effective anti-cancer therapies. Additionally, addressing these questions will: 1. Further define the unrecognized role of FOXO and JNK signaling pathways in cancer biology. 2. Provide novel proof-of-concept strategies for the treatment and diagnosis of AML. 3. Improve our understanding of the molecular networks that support human leukemogenesis in vivo.
| Di Marcantonio, Daniela; Martinez, Esteban; Sidoli, Simone et al. (2018) Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia. Clin Cancer Res 24:608-618 |
| Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406 |
| Maifrede, Silvia; Martinez, Esteban; Nieborowska-Skorska, Margaret et al. (2017) MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs. Blood Adv 1:1467-1472 |
| Zhou, C; Martinez, E; Di Marcantonio, D et al. (2017) JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia. Leukemia 31:1196-1205 |
| Sykes, Stephen M; Kokkaliaris, Konstantinos D; Milsom, Michael D et al. (2015) Clonal evolution of preleukemic hematopoietic stem cells in acute myeloid leukemia. Exp Hematol 43:989-92 |
| Lee, Dongjun; Sykes, Stephen M; Kalaitzidis, Demetrios et al. (2014) Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors. Stem Cell Reports 3:832-40 |
| Saez, Borja; Ferraro, Francesca; Yusuf, Rushdia Z et al. (2014) Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 124:2937-47 |
| Limon, Jose J; So, Lomon; Jellbauer, Stefan et al. (2014) mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc Natl Acad Sci U S A 111:E5076-85 |
| Placke, Theresa; Faber, Katrin; Nonami, Atsushi et al. (2014) Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 124:13-23 |
| Sykes, Stephen M; Scadden, David T (2013) Modeling human hematopoietic stem cell biology in the mouse. Semin Hematol 50:92-100 |
Showing the most recent 10 out of 13 publications
