EDUCATION
- Northwestern University, Feinberg School of Medicine, Tumor Biology (Ph.D), 2006
- University of Illinois at Urbana-Champaign, Ecology, Ethology, and Evolution (B.S), 1999.
- College of DuPage, Associate Degree in Arts (AA), Associate Degree in Science (AS), 1997.
RESEARCH SUMMARY
Understanding the fundamental molecular mechanisms underlying megakaryocytic differentiation and polyploidization is an essential first step to discovering novel therapeutic targets and approaches for treating Mk and platelet disorders such as essential thrombocytopenia, refractory thrombocytopenia in myelodysplastic syndromes, megakaryoblastic leukemia, and thrombocythemia. Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell disorders often accompanied by defective megakaryocyte (Mk) development, decreased platelet counts, and often progress into leukemia. Most MDS patients have chronic thrombocytopenia, but platelet transfusion is complicated by the development of allogeneic antibodies and ca. 30% of MDS patients die of bleeding. Therefore, increased endogenous platelet production could extend the lifespan (and increase the quality of life) for a substantial fraction of MDS patients by rescue from and/or delayed onset of clinically significant thrombocytopenia. Unfortunately, little information is known about Mk (platelet precursors) or platelet production. Because the number of platelets released by a single Mk is directly proportional to how much DNA the cell contains, understanding the Mk cell cycle may provide crucial insights and allow for better platelet expansion.
Well-known as a "toxic sensor," aryl hydrocarbon receptor (AhR) function is normally associated with the action mechanism of various environmental toxins, presumably by altering cell cycle regulation. Environmental exposure to high levels of AhR ligands has been associated with increased platelet counts and we hypothesize that as a cell cycle regulator, AhR may impact Mk polyploidization, a process known to involve a modified cell cycle. Our data indicate that AhR expression and activity increases during Mk differentiation of both cell lines and primary human CD34+ cells and coincides with increased target gene expression. Importantly, AhR RNAi knockdown results in decreased Mk polyploidization through unknown mechanisms. We propose to (1) test the hypothesis that AhR is required for the formation ofproplatelet extensions and in vivo platelet production and function, (2) further investigate if AhR is activated and necessary for megakaryopoiesis, leading to increased Mk polyploidization; (3) determine if AhR-mediated Hes1 expression regulates the level and localization of cyclin D3, cyclin E, and other key Mk genes during megakaryopoiesis; Our experiments could simultaneously provide important insights into megakaryopoiesis by identifying a novel thrombocytopenic event (reduced AhR), and guide new treatment options to increase platelet counts (drugs and/or treatments that increase AhR activity) in thrombocytopenic patients.
HONORS AND RECOGNITION
- 2010-2012 American Society of Hematology Trainee Council
- 2009-2012 NIH NRSA individual postdoctoral fellowship (F32HL091620)
- 2009 American Society of Hematology Travel Award
- 2009 Strathmore's Who's Who
- 2003-2005 Northwestern University Carcinogenesis Training Grant (NIH-T32CA09560).
- 1996 American Legion Good Citizenship Citation
- 1995-1997 B.J. Hoddinot Earth Science Scholarship (full academic scholarship)
- 1995 National Dean’s List
- 1994 Eagle Scout
SELECTED PUBLICATIONS
- Lindsey S, Papoutsakis ET. (2011) The Aryl Hydrocarbon Receptor (AhR) Transcription Factor Regulates Polyploidization During Megakaryocytic Differentiation. British Journal of Haematology 152:469-84. <Pubmed>
- Giammona LM, Panuganti S, Kemper JM, Apostolidis PA, Lindsey S, Papoutsakis ET, Miller WM. (2009) Mechanistic studies on the effects of nicotinamide on megakaryocytic polyploidization and the roles of NAD+ levels and SIRT inhibition. Experimental Hematology 37:1340-1352. <Pubmed>
- Wang H*, Lindsey S*, Konieczna I, Bei L, Horvath E, Huang W, Saberwal G, Eklund EA. (2009) Constitutively active SHP2 cooperates with HoxA10-overexpression to induce acute myeloid leukemia. Journal of Biological Chemistry 284:2549-2567. <Pubmed>
- Fuhrken P, Apostolidis P, Lindsey S, Miller WM, and Papoutsakis ET. (2008) Tumor suppressor protein p53 regulates megakaryocytic endomitosis and apoptosis. Journal of Biological Chemistry 283:15589-15600. <Pubmed>
- Zhu C*, Lindsey S*, Konieczna I, Eklund EA. (2008) Constitutive Activation of SHP2 Protein Tyrosine Phosphatase Inhibits ICSBP-Induced Transcription of the Gene Encoding gp91PHOX During Myeloid Differentiation. Journal of Leukocyte Biology 83:680-691. <Pubmed>
- Konieczna I, Horvath E, Wang H, Lindsey S, Saberwal G, Bei L, Huang W, Platanias L, Eklund EA. (2008) Constitutive activation of SHP2 cooperates with ICSBP-deficiency to accelerate progression to acute myeloid leukemia. Journal of Clinical Investigation 118:853-867. <Pubmed>
- Lindsey S, Huang W, Wang H, Horvath E, Zhu C, Eklund EA. (2007) Activation of SHP2 Protein Tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX. Journal of Biological Chemistry 282:2237-2249. <Pubmed>
- Huang W, Saberwal G, Horvath E, Zhu C, Lindsey S, Eklund EA. (2006) Leukemia-Associated, Constitutively Active Mutants of SHP2 Protein Tyrosine Phosphatase Inhibit NF1 Transcriptional Activation by the Interferon Consensus Sequence Binding Protein. Molecular and Cellular Biology 26:6311-6332. <Pubmed>
- Lindsey S, Zhu C, Lu YF, Eklund EA. (2005) HoxA10 Represses Transcription of the Gene Encoding p67PHOX in Phagocytic Cells. Journal of Immunology 175:5269-5279. <Pubmed>
- Petersen CE, Lindsey SC, Dudgeon DM, and Pertell RA. (1998) The Effect of Seed Predation on Pod Abortion by the Prairie Legume, Baptisia leucophaea. Transactions of the Illinois State Academy of Science 91:47-52. <Pdf>
RESEARCH SUMMARY KEYWORDS
- Aryl Hydrocarbon Receptor (AHR)
- Hematopoiesis
- Megakaryocyte
- Differentiation
- Leukemia
