D. Wade Clapp, M.D.
Richard L. Schreiner Professor and Chairman, Department of Pediatrics
Professor Microbiology & Immunology
Professor Biochemistry & Molecular Biology
Description and summary of research focus of the laboratory
Dr. Clapp's laboratory is focused on understanding the molecular pathogenesis of two genetic diseases that result in both hematopoietic malignancies as well as solid tumors. One major area of interest is to understand the role of the NF1 tumor suppressor gene. Mutations in NF1 cause the common genetic disorder neurofibromatosis type 1 (NF1) which is associated with a predisposition to neural crest derived tumors and juvenile myelomonocytic leukemia (JMML). Neurofibromin, the protein product of the NF1 gene, functions at least in part as a GTPase activating protein that regulates Ras proteins by stimulating their intrinsic GTPase activity. Haploinsufficiency of NF1, via its role in lineages of the tumor microenvironment, is becoming increasingly recognized for its involvement in tumor progression in malignancies affecting individuals with NF1. Dr. Clapp's laboratory provided the first genetic evidence that haploinsufficiency of NF1 alters cell fates in lineages implicated in the disease pathogenesis of neurofibromatosis type 1 (Ingram, JEM 2000). Subsequent work identified a mechanism for how mast cells are recruited to the emerging tumor microenvironment (Yang, JCI 2003). Most recently he and his collaborators have demonstrated a key role for the hematopoietic system and the c-kit/kit ligand pathway in plexiform neurofibroma tumor progression (Yang, Cell 2008). These results have led to a phase 2 clinical trial currently in progress under the direction of Dr. Kent Robertson. Ongoing work is focused on both understanding additional paracrine interactions in the growth of plexiform neurofibromas and in identifying additional molecular targets involved in tumor progression.
Dr. Clapp's group is also interested in the cellular and biochemical functions of an orphan group of proteins that are involved in the heterogenetic disorder Fanconi Anemia. Fanconi anemia (FA) is a rare heterogeneous genetic disorder composed of at least 13 complementation groups. The disease is characterized by a progressive bone marrow aplasia, chromosomal instability, hypersensitivity to bi-functional alkylating agents and the acquisition of malignancies, including a high predisposition for hematopoietic malignancies. Dr. Clapp's laboratory is focusing on understanding the molecular mechanisms that underlie the genesis of the bone marrow failure and clonal evolution of hematopoietic malignancies. Investigators in his lab have recently generated unique murine models to address these questions. A second area of emphasis is in the development of gene transfer and transplantation protocols to optimize gene transfer and engraftment of FA deficient cells using murine models. Dr. Clapp and his collaborators are currently developing modified foamyviral and lentiviral vector delivery systems that appear to have several advantages over traditional retroviruses.
- Molosh AI, Johnson PL, Spence JP, Arendt D, Federici LM, Bernabe C, Janasik SP, Segu ZM, Khanna R, Goswami C, Zhu W, Park SJ, Li L, Merchref YS, Clapp DW, Shekhar A. Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci. 2014 Sept 21. doi: 10.1038/nn.3822 [Epub ahead of print] PMID: 252422307
- De Raedt T, Beert E, Pasmant E, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, Mautner V, Kehrer-Sawatzki H, Clapp W, Bradner J, Vidaud M, Upadhyaya M, Legius E, Cichowski K. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct. 9; 514(7521);247-51. doi: 10.1038/nature13561. Epub 2014 Aug 13. PMID: 25119042
- Nalepa G, Enzor R, Sun Z, Marchal C, Park SJ, Yang Y, Tedeschi L, Kelich S, Hanenberg H, Clapp DW. Fanconi anemia signaling network regulates the spindle assembly checkpoint. J Clin Invest 2013 Sep 3; 123(9);3839-47. doi: 10.1172/JCI67364. Epub 2013 Aug 15. PMID: 23934222
- Nalepa G, Barnholtz-Sloan J, Enzor R, Dey D, He Y, Gehlhausen JR, Lehmann AS, Park SJ, Yang Y, Yang X, Chen S, Guan S, Guan X, Chen Y, Renbarger J, Yang FC, Parada LF, Clapp W. The tumor suppressor CDKN3 controls mitosis. J Cell Biol. 2013 Jun 24;201(7):997-1012. doi/jcb.201205125. Epub 2013 June 17. Erratum in: J Cell Bio. 2013 Aug 19;202(4):717. PMID: 23775190.
- Staser K, Park SJ, Rhodes SD, Zeng Y, He YZ, Shew MA, Gehlhausen JR, Cerabona D, Menon K, Chen S, Sun Z, Yuan J, Ingram DA, Nalepa G, Yang FC, Clapp DW. Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest. 2013 Jan 2; 123(1):329-34. doi: 10.1172/JCI66167. Epub 2012 Dec 10. PMID: 23221339
- Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY, Hutchins GD, Croop JM, Vik TA, Denne SC, Parada LF, Hingtgen CM, Walsh LE, Yu M, Pradhan KR, Edwards-Brown MK, Cohen MD, Fletcher JW, Travers JB, Staser KW, Lee MW, Sherman MR, Davis CJ, Miller LC, Ingram DA, Clapp DA. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromastosis type 1: a phase 2 trial. Lancel Oncol. 2012 Dec 13(12): 1218-24. doi: 10.1016/S1470-2045(12)70414-X. Epub 2012 Oct 23. PMID: 23099009
- Staser K, Shew MA, Michels EG, Mwanthi MM, Yang FC, Clapp DW, Park SJ. A Pak 1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol. 2013 Jan;41(1):56-66.e2. doi: 10.1016/j.exphem.2012.10.001. Epub 2012 Oct 11. PMID: 23063725
- Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood. 2010 Jul 15; 116(2):157-64. doi: 10.1182/blood-2009-09-242875. Epub 2010 Mar 16. Review. PMID: 20233971
- Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertston K, Hutchins G, Parada LF, Clapp DW. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008 Oct 31; 135(3):437-48. doi: 10.1016/j.cell.2008.08.041. PMID: 18984156
- Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, Clegg T, White H, Mead L, Wenning MJ, Williams DA, Kapur R, Atkinson SJ, Clapp DW. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for NF1 +/-- mast cells. J Clin Invest. 2003 Dec; 112(12):185-61. PMID: 14679180
- M.D.,1982, Indiana University School of Medicine, Indianapolis, IN
- Residency, 1982 - 1985, Pediatrics, Indiana University School of Medicine, Indianapolis, IN,
- Chief Resident, 1985 - 1986, Pediatrics, Indiana University School of Medicine, Indianapolis, IN,
- Fellow, 1986 - 1989, Neonatology, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH,
- Fellow, 1989 - 1990, Laboratory of Stanton L. Gerson, Hematopoiesis Core Facility Ireland Cancer Center, Case Western University, Cleveland, OH