Laboratory of Seth Corey, M.D, M.P.H.
Seth Corey’s laboratory studies the cellular, molecular, organismal, and mathematical basis for normal and abnormal hematopoiesis. Focusing on the inherited bone marrow failure syndromes as “experiments of nature”, Corey lab’s work investigates neutrophils, a critical component of the innate immune response, and their precursors.
Dr. Corey is the principal investigator on a new NIH R01 that integrates biological experimental data with mathematical modeling and computer simulation for revealing the steps in transformation from severe congenital neutropenia to myelodysplastic syndrome (MDS) to acute myeloid leukemia. Severe congenital neutropenia typically results from mutations in ELANE, a protease. A second mutation involves the gene for granulocyte colony stimulating factor receptor (GCSFR). Ongoing studies examine the role played by the unfolded protein response (UPR) induced by mutant ELANE, the effect of oxidative stress and UPR stress on genomic instability and mutation of the GCSFR, differential signal transduction at phosphoprotein and gene expression (RNA-Seq) levels, and clonal growth advantages as measured by DNA barcoding. Patient-derived iPS cells are being studied. Mathematical modeling involving branching processes and computational construction of signaling based on graph theory are also employed.
Splicing mutations are the most common recurrent mutations in MDS. Funded by a grant from the DOD, Corey’s lab is studying how splicing affects the production of GCSFR isoforms. One alternatively spliced form is differentiation-defective and is associated with myeloid leukemia. Projects include: identifying specific splicing factor and its post-translational modification that affect GCSFR and reconstitution in mice of a differentiation-defective GCSFR.
Another major project in the lab funded by NIH R21 and other foundations is modeling human bone marrow failure and leukemogenesis in zebrafish. Using CRISPR/Cas9 editing, several strains of zebrafish have been created that phenocopy closely the human Shwachman-Diamond Syndrome (SDS). Due to defective ribosomal function, SDS is characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and leukemia predisposition. A gata2-deficient zebrafish is also being developed. GATA2-deficiency is also a leukemia-predisposing inherited bone marrow failure syndrome that also involves lymphatic formation, monocytes, and natural killer cell number and function.
Wilmer Amaya-Mejia, BS
Frances Austin, MD
Bhavuk Garg, PhD
Ralph Kemal, MD
Hrishikesh “Rishi” Mehta, PhD
Usua Oyarbide, PhD
Abigail Oyelayo, BS
Borwyn “Ann” Wang, BS
Corey SJ, Eguinoa A, Puyana-Theall K, Bolen JB, Cantley L, Mollinedo F, Jackson TR, Hawkins PT, Stephens LP. Granulocyte-macrophage-colony stimulating factor stimulates both activation and association of phosphatidylinositol 3OH-kinase and src-related tyrosine kinase(s) in human myeloid-derived cells. EMBO J 12:2681-2690, 1993. PMID: 8392933.
Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ. G-CSF receptor signaling involves the formation of a three-component complex with lyn and syk protein-tyrosine kinases. Proc Natl Acad Sci USA 91:8634-8637, 1994. PMID: 8197119.
Redner RL, Rush E, Faas S, Ruddert W, Corey SJ. The t(5;17) translocation in acute promyelocytic leukemia fuses nucleophosmin to RAR. Blood 87:882-886, 1996. PMID: 8562957.
Corey SJ, Minden M, Barber D, Kantarjian H, Wang J, Schimmer AD. Myelodysplastic Syndromes – stem cell diseases of complexity. Nat Rev Cancer, 7:118-129, 2007. PMID: 17251918.
Andolina JR, Morrison CB, Thompson AA, Chaudhury S, Mack AK, Proytcheva M, Corey SJ. Shwachman-Diamond syndrome: diarrhea, no longer required. J Pediatr Hematol Oncol 35:486-9. 2013. PMID: 22935661.
Guerrouahen BS, Vaklavas C, Kanerva J, Nwawka K, Blanchard EG, Lee FY, Robinson LJ, Arceci R, Kornblau SM, Wieder E, Corey SJ. Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. Clin Can Res, 16:1149-1158, 2010. PMID: 20145167. PMCID: PMC2988651.
Glaubach T, Minella AC, Corey SJ. Cellular stress pathways in pediatric bone marrow failure syndromes – Many roads lead to neutropenia. Pediatr Res 75:189-95, 2014. PMID: 24192702.Tidwell T, Wechsler J, Nayak R, Trump L, Salipante SJ, Cheng JC, Glaubach T, Corey SJ, Grimes HL, Kutzko C, Cancelas JS, Horwitz MS. Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms. Blood, 23:562-9, 2014. PMID: 24184683 (chosen for Inside Blood commentary by editors of Blood).Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in Neutropenia. J Immunol 195:1341-9, 2015. PMID: 26254266.Mehta H, Glaubach T, Long A, Lu H, Przychodzen B, Mikashima H, Cross NP, Maciejewski JP, Corey SJ. Granulocyte Colony Stimulating Factor Receptor T595I confers ligand-independence and enhanced signaling. Leukemia, 27: 2407-10, 2013. PMID: 23739288.
Mehta H, Futami M, Glaubach T, Lee DW, Andolina J, Whichard Z, Quinn M, Kao WM, Przychodzen B, Sarkar C, Minella AM, Maciejewski JP, Corey SJ. Alternatively-spliced, truncated GCSF Receptor promotes leukemogenic properties and sensitivity to JAK inhibition. Leukemia 28:1041-51, 2014 PMID: 24170028.
Whichard Z, Sarkar CA, Kimmel M, Corey SJ. Hematopoiesis and its disorders – a systems biology approach. Blood, 115:2339-47, 2010. PMID: 20103779.
Kimmel M, Corey SJ. Stochastic hypothesis of transition from inborn neutropenia to AML: Interactions of cell population dynamics and population genetics. Front Onc 3:89,2013. PMID: 23641360.
Feng Y, Hartig SM, Bechill JE, Blanchard EG, Caudell EG, Corey SJ. The Cdc42 Interacting Protein 4 (CIP4) Gene Knockout Mouse Reveals Delayed and Decreased Endocytosis. J Biol Chem, 285:4348-4354, 2010. PMID: 19920150. PMCID: PMC2836039.
Pichot CS, Hartig SM, Arvanitis C, Jensen S, Bechill J, Marzouk S, Yu J, Frost JA, Corey SJ. Cdc42 interacting protein promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASP. Cancer Res 70:8347-8356 2010. PMID: 20940394.
Chen Y, Aardema J, Kale S, Whichard ZL, Awomolo A, Blanchard E, Chang B, Myers DR, Ju L, Tran R, Reece D, Christensen H, Boukour S, Debili N, Strom TS, Rawlings D, Vázquez FX, Voth GA, Zhu C, Kahr WH, Lam WA, Corey SJ. Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling. Blood 122:1695-7062013 PMID: 2388191 (chosen as Plenary Paper).