Stephen M. Sykes, PhD
Office Phone: 215-728-3539
Lab Phone: 215-728-3563
Our primary focus is to decipher the molecular abnormalities that contribute to the pathogenesis of blood diseases such as myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately one third of patients diagnosed with MDS eventually develop AML and less than 1 in 4 patients diagnosed with AML survive beyond 5 years. These poor statistics combined with the inadequacies and toxicities of current therapies underscores the pressing need to develop new, more effective therapies to treat these diseases.
A common first step in the development of new therapies for any disease begins by identifying the causative genetic abnormalities and then designing compounds that eliminate or correct the respective mutant gene product. The prevailing notion is that such targeted therapies will selectively kill diseased cells and leave normal tissues unharmed. However, designing targeted therapies against many blood malignancies is complicated by two major factors. First, a small but distinct fraction of leukemia cells are able to evade conventional drugs and cause leukemia relapse (often referred to as leukemia-initiating cells (LICs) or leukemia stem cells (LSCs)). Second, the ability to design broad-spectrum anti-leukemia drugs is limited by the extensive genetic diversity that is seen in myeloid leukemia and pre-malignant blood syndromes. Therefore, identifying and targeting molecular aberrations that support LICs across a wide-spectrum of myeloid malignancies is critical for developing successful broad-based anti-leukemia therapies.
We have recently identified that the FOXO family of tumor suppressive transcription factors play a supportive role in a significant portion of AMLs. Using a gene expression dataset derived from a large cohort of human AML samples, 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 LIC function and survival. Further investigation revealed that approximately 60% of the leukemic samples were resistant to FOXO suppression. Those cells that were FOXO insensitive had abnormalities in another pathway, the JNK family of kinases. Compounds that inhibit JNK enzymes caused marked killing of cancer cells resistant to FOXO inhibition indicating that the JNK pathway may help leukemia cells overcome the need for functional FOXO activities. We are currently investigating the downstream effectors of the FOXO and JNK pathways that help them support leukemogenesis.Description of research projects
Fox Chase Programs
- Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SA, Scholl C, Tothova Z, Attar E, Frohling S, DePinho RA, Gilliland DG, Armstrong SA, Scadden DT (2011). AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011 Sep 2;146(5):697-708.
- Ferraro F, Lymperi S, Mendez-Ferrer S, Saez B, Spencer JA, Yeap BY, Masselli E, Graiani G, Prezioso L, Lodi-Rizzini E, Mangoni M, Rizzoli V, Sykes SM, Lin CP, Frenette PS, Quaini F, Scadden DT. Diabetes Impairs Hematopoietic Stem Cell Mobilization Through Alteration of Niche Function. Sci Transl Med. 2011 Oct 12;3(104):104ra101.
- Cornejo MG*, Mabialah V*, Sykes SM*, Khandan T, Lo Celso C, Lopez C, Rivera- Muñoz P, Rameau P, Tothova Z, Aster JC, DePinho RA, Scadden DT, Gilliland DG, Mercher T. Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification. Blood. 2011 Aug 4;118(5):1264-73.
- Lane SW, Wang YJ, Lo Celso C, Ragu C, Bullinger L, Sykes SM, Ferraro F, Shterental S, Lin CP, Gilliland DG, Scadden DT, Armstrong SA, Williams DA. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011 Sep 8;118(10):2849-56.
- Lane SW, Sykes SM, Al-Shahrour F, Shterental S, Paktinat M, Lo Celso C, Jesneck JL, Ebert BL, Williams DA, Gilliland DG (2010). The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood. 2010 Apr 29;115(17):3489-97.