Introduction
I have over thirty years of experience in academic dermatopathology and skin morphology, and a long history of use and early adaptation of most advanced techniques including immuno-electron microscopy, direct and indirect immunofluoresence, multiple chromagen immunohistochemical and immunofluoresence staining, in situ hybridization and in situ transcription, and laser micro-dissection and sequencing. I was lead author on the first published study of extraction and amplification of nucleic acids from archival formalin fixed skin samples.I have established expertise in melanoma and dysplastic nevi, and attended the NIH Consensus Conference on early precursors of melanoma where terminology and criteria for diagnosis and management of dysplastic nevi were established (Diagnosis and treatment of early melanoma. NIH Consensus Development Conference. 1992 Jan 27-29;10(1):1-25. PMID:1515516). I served as a Beta tester for the Vysis® melanoma multi-spectral fluorescence in situ hybridization (FISH) test recently developed by Abbott laboratories and Dr. Boris Bastian.
As Director of Dermatopathology at UW, I have access to over 200,000 paraffin embedded skin specimens including thousands of dysplastic nevi and hundreds of melanomas that served as the basis for the TMA that I helped create with fellow UW faculty Vijay Setaluri and Wei Huang.I have extensive experience directing academic Dermatopathology laboratories at Yale and UW Madison, and for two years directed the Department of Comparative Medicine Histopathology Laboratory (animal pathology lab) at Yale University School of Medicine.
In my own work I have analyzed the histopathology of spontaneous canine tumors, and studied mice with induced tumors and tumor grafts including syngenic and xenografted tumors. I have evaluated murine infections and inflammatory responses, and made and analyzed genetically altered mice with skin phenotypes such as the transgenic K14::Kit Ligand mice which have epidermal melanocytes similar to human epidermal melanocytes.
I am the Director of the Experimental Cutaneous Pathology Core (ECPC) of the newly established, NIH-funded UW Skin Disease Research Center (UW SDRC). The overall goal of the Experimental Cutaneous Pathology Core (ECPC) is to promote cutaneous research by providing UW SDRC members with carefully processed normal and diseased human skin samples, and expertise for morphologic analysis of human and animal skin and skin-related tissue. ECPC leadership includes Dr. Ruth Sullivan, a board-certified veterinary pathologist who specializes in the pathology of genetically altered rodents. Our core has the necessary expertise to provide excellent analysis of MmuPV1-infected mouse tissue, and as a member of the UW SDRC, Paul Lambert will receive these services at a subsidized rate over non-members. I am certain that my core service will be able to contribute to the excellent direction of Dr. Lambert’s project.
Establishing mastocytosis as an oncogene driven neoplasia
In the past there was controversy as to whether mastocytosis was a neoplastic or a reactive process. I was the first to show that most human mastocytosis is a clonal, neoplastic process characterized by kinase domain mutations that cause ligand independent activation of the KIT receptor tyrosine kinase.
Discovery and characterization of the intracellular-juxtamembrane class of KIT activating mutations
I was also the first show that different, clinically relevant types of KIT mutations may cause spontaneous activation of KIT kinase. At the time it was known that mutations of the kinase domain activation loop can cause spontaneous tyrosine kinase activation. In these studies I identified an intercellular juxta-membrane helical region that suppresses activation of ligand un-occupied KIT. I found that helix breaking mutations of this region cause ligand independent activation of the KIT kinase without changing the structure of the kinase site, and were therefore responsive to drugs targeting wild type KIT, such as Imatinib produced by Novartis.
At that time I had agreed to sponsor a clinical trial for Novartis based on their report to me that a human mast cell line was responsive to Imatinib. Just as the drug samples were being prepared for shipping I found that their cell line contained only a juxta-membrane activation mutation and was therefore responsive to Imatinib, but a similar cell line that expressed the kinase domain activation loop activating mutation found in most human mastocytosis was resistant to Imatinib. This led to cancellation of the trial, preventing risk to the patients and significant expense.
Discovery of human epidermal keratinocyte KIT ligand and creation of humanized K14-KIT ligand transgenic mice with epidermal melanocytes
Melanocytes in normal mouse skin reside mostly in the hair bulb and are rarely found in the epidermis. I discovered that, unlike mice, human epidermal keratinocytes express cell surface KIT Ligand, a melanocyte growth factor also known as stem cell factor and mast cell growth factor. Using a transgenic approach we found that epidermal expression of KIT Ligand was both necessary and sufficient to cause melanocytes to populate and persist in the epidermis. The “humanized” mice we developed from these studies have been useful for studies of melanocyte biology including development of the best murine model of vitiligo.
We also discovered that the mast cell enzyme chymase solubilizes membrane bound keratinocyte KIT Ligand, thereby stimulating melanocyte melanin production and lowering the threshold for mast cell degranulation, and may play a role in contact dermatitis. Solubilization of keratinocyte KIT Ligand also explains why human cutaneous mastocytosis lesions are pigmented.
Team
![]() Principal Investigator bjlongley@dermatology.wisc.edu |
![]() Associate Scientist nalrayyan@dermatology.wisc.edu |
![]() Associate Scientist thsiao@dermatology.wisc.edu |
Contact
(For research-related inquiries only. Patients and others with medical questions should call 608-287-2620)
bjlongley@dermatology.wisc.edu
608-263-4195
Location
436 Medical Sciences Center
1300 University Ave
Madison, WI 53706