Photo of David Sykes,  MD, PhD

David Sykes, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-4000


dbsykes@partners.org

David Sykes, MD, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Instructor, Medicine, Harvard Medical School
  • Hematologist, Cancer Center / Hematology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Acute myeloid leukemia (AML) remains a devastating disease in adults, with an overall survival rate of 30%, despite advances in supportive care and allogeneic stem cell transplantation. One of the rare success stories in AML was the development of differentiation therapy in the form of retinoic acid for the small subset (10%) of patients with acute promyelocytic leukemia (APL). While APL was once the subtype with the worst prognosis, it is now the best prognosis with an overall survival exceeding 85%.

Differentiation therapy does not exist for the remaining 90% of patients with AML, and the standard of care chemotherapy (cytarabine + an anthracycline) has not changed in more than thirty years.

My goal is to identify and develop differentiation therapy for the treatment of patients with acute myeloid leukemia.

Publications

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  • Kalaitzidis D, Lee D, Efeyan A, Kfoury Y, Nayyar N, Sykes DB, Mercier FE, Papazian A, Baryawno N, Victora GD, Neuberg D, Sabatini DM, Scadden DT. Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Invest 2017; 127:1405-1413. PubMed
  • Hahm E, Wei C, Fernandez I, Li J, Tardi NJ, Tracy M, Wadhwani S, Cao Y, Peev V, Zloza A, Lusciks J, Hayek SS, O'Connor C, Bitzer M, Gupta V, Sever S, Sykes DB, Scadden DT, Reiser J. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 2016; 23:100-106. PubMed
  • Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL. Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia. 2016; 7:1112-1117. PubMed
  • Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, Meyer H, Pierce KA, Tolliday NJ, Waller A, Ferrara SJ, Eheim AL, Stoeckigt D, Maxcy KL, Cobert JM, Bachand J, Szekely BA, Mukherjee S, Sklar LA, Kotz JD, Clish CB, Sadreyev RI, Clemons PA, Janzer A, Schreiber SL, Scadden DT. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 2016; 167:171-186.e15. PubMed
  • Mercier FE, Sykes DB, Scadden DT. Single Targeted Exon Mutation Creates a True Congenic Mouse for Competitive Hematopoietic Stem Cell Transplantation: The C57BL/6-CD45.1(STEM) Mouse. Stem Cell Reports 2016; 6:985-92. PubMed
  • Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, Czechowicz A, Kfoury Y, Ruchika F, Rossi DJ, Verdine GL, Mansour MK, Scadden DT. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 2016. PubMed
  • Lee D, Wang YH, Kalaitzidis D, Ramachandran J, Eda H, Sykes DB, Raje N, Scadden DT. Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy. J Clin Invest 2016; 126:1300-10. PubMed
  • Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, Jo SH, Weins A, Hakroush S, Cebulla A, Sykes DB, Greka A, Mundel P, Fisher DE, Mandinova A, Lee SW. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 2015; 349:1261669. PubMed
  • Wu L, Walas S, Leung W, Sykes DB, Wu J, Lo EH, Lok J. Neuregulin1-β decreases IL-1β-induced neutrophil adhesion to human brain microvascular endothelial cells. Transl Stroke Res 2015. PubMed
  • Gupta S, Fenves A, Nance ST, Sykes DB, Dzik WS. Hyperhemolysis syndrome in a patient without a hemoglobinopathy, unresponsive to treatment with eculizumab. Transfusion 2015. PubMed
  • Rosado FG, Oliveira JL, Sohani AR, Schroyens W, Sykes DB, Kenderian SS, Lacy MQ, Kyle RA, Hoyer JD. Bone marrow findings of the newly described TEMPI syndrome: when erythrocytosis and plasma cell dyscrasia coexist. Mod Pathol 2015. PubMed
  • Khan J, Sykes DB. Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting. BMC Hematol 2014; 14:11. PubMed
  • Mansour MK, Tam JM, Khan NS, Seward M, Davids PJ, Puranam S, Sokolovska A, Sykes DB, Dagher Z, Becker C, Tanne A, Reedy JL, Stuart LM, Vyas JM. Dectin-1 activation controls maturation of β-1,3-glucan-containing phagosomes. J Biol Chem 2013; 288:16043-54. PubMed
  • Simic P, Zainabadi K, Bell E, Sykes DB, Saez B, Lotinun S, Baron R, Scadden D, Schipani E, Guarente L. SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin. EMBO Mol Med 2013; 5:430-40. PubMed
  • Singh H, Lane AA, Correll M, Przychodzen B, Sykes DB, Stone RM, Ballen KK, Amrein PC, Maciejewski J, Attar EC. Putative RNA-splicing gene LUC7L2 on 7q34 represents a candidate gene in pathogenesis of myeloid malignancies. Blood Cancer J 2013; 3:e117. PubMed
  • Schroyens W, O'Connell C, Sykes DB. Complete and partial responses of the TEMPI syndrome to bortezomib. N Engl J Med 2012; 367:778-80. PubMed
  • Park D, Sykes DB, Scadden DT. The hematopoietic stem cell niche. Front Biosci (Landmark Ed) 2011; 17:30-9. PubMed
  • Sykes DB, Schroyens W, O'Connell C. The TEMPI syndrome--a novel multisystem disease. N Engl J Med 2011; 365:475-7. PubMed
  • Scheele JS, Kolanczyk M, Gantert M, Zemojtel T, Dorn A, Sykes DB, Sykes DP, Möbest DC, Kamps MP, Räpple D, Duchniewicz M. The Spt-Ada-Gcn5-acetyltransferase complex interaction motif of E2a is essential for a subset of transcriptional and oncogenic properties of E2a-Pbx1. Leuk Lymphoma 2009; 50:816-28. PubMed
  • Odegaard JI, Vats D, Zhang L, Ricardo-Gonzalez R, Smith KL, Sykes DB, Kamps MP, Chawla A. Quantitative expansion of ES cell-derived myeloid progenitors capable of differentiating into macrophages. J Leukoc Biol 2007; 81:711-9. PubMed
  • Wang GG, Calvo KR, Pasillas MP, Sykes DB, Häcker H, Kamps MP. Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nat Methods 2006; 3:287-93. PubMed
  • Sykes DB, Kamps MP. E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice. Mol Cell Biol 2004; 24:1256-69. PubMed
  • Sykes DB, Scheele J, Pasillas M, Kamps MP. Transcriptional profiling during the early differentiation of granulocyte and monocyte progenitors controlled by conditional versions of the E2a-Pbx1 oncoprotein. Leuk Lymphoma 2003; 44:1187-99. PubMed
  • Sykes DB, Kamps MP. Estrogen-regulated conditional oncoproteins: tools to address open questions in normal myeloid cell function, normal myeloid differentiation, and the genetic basis of differentiation arrest in myeloid leukemia. Leuk Lymphoma 2003; 44:1131-9. PubMed
  • Welch JS, Escoubet-Lozach L, Sykes DB, Liddiard K, Greaves DR, Glass CK. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J Biol Chem 2002; 277:42821-9. PubMed
  • Calvo KR, Sykes DB, Pasillas MP, Kamps MP. Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene 2002; 21:4247-56. PubMed
  • Klappacher GW, Lunyak VV, Sykes DB, Sawka-Verhelle D, Sage J, Brard G, Ngo SD, Gangadharan D, Jacks T, Kamps MP, Rose DW, Rosenfeld MG, Glass CK. An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation. Cell 2002; 109:169-80. PubMed
  • Calvo KR, Knoepfler PS, Sykes DB, Pasillas MP, Kamps MP. Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia. Proc Natl Acad Sci U S A 2001; 98:13120-5. PubMed
  • Sykes DB, Kamps MP. Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins. Blood 2001; 98:2308-18. PubMed
  • Knoepfler PS, Sykes DB, Pasillas M, Kamps MP. HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation. Oncogene 2001; 20:5440-8. PubMed
  • Slupsky CM, Sykes DB, Gay GL, Sykes BD. The HoxB1 hexapeptide is a prefolded domain: implications for the Pbx1/Hox interaction. Protein Sci 2001; 10:1244-53. PubMed
  • Calvo KR, Sykes DB, Pasillas M, Kamps MP. Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression. Mol Cell Biol 2000; 20:3274-85. PubMed
  • Parney IF, Petruk KC, Zhang C, Farr-Jones M, Sykes DB, Chang LJ. Granulocyte-macrophage colony-stimulating factor and B7-2 combination immunogene therapy in an allogeneic Hu-PBL-SCID/beige mouse-human glioblastoma multiforme model. Hum Gene Ther 1997; 8:1073-85. PubMed
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