Redefining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying Biomarkers for Early Detection and Risk Assessment. This application addresses Program Announcement PA-09-197: Biomarkers for Early Detection of Hematopoietic Malignancies (R01). The overall aim of this project is to identify novel biomarkers that may be used to diagnose and treat patients with Langerhans Cell Histiocytosis (LCH). LCH occurs with similar frequency as other rare malignancies including Hodgkin's lymphoma and AML. However, unlike other neoplastic white blood cell disorders, little is known about the etiology of LCH. Due to the current lack of in vitro or animal models, research currently relies on study of primary tissue. We have developed the world's largest Histiocytosis Center at Baylor College of Medicine with over 100 new diagnoses annually, allowing us to create a large bank of LCH tissues and plasma. With these invaluable biological resources and novel lab techniques, we are now able to ask fundamental questions regarding cell-specific gene expression and the cell of origin of LCH. The current model of LCH suggests that pathologic Langerhans cells in LCH lesions arise due to malignant transformation of epidermal Langerhans cells. However, our preliminary cell-specific gene expression experiments from LCH lesions found that pathologic Langerhans cells highly express genes associated with immature myeloid cells and have transcription profiles distinct from normal epidermal Langerhans cells. We therefore propose the hypothesis that LCH is a myeloid dysplasia that arises from bone-marrow derived circulating myeloid dendritic cells (mDCs). This hypothesis will be tested with the following Aims:
Specific Aim 1 : Identify unique circulating immature mDC populations in peripheral blood from patients with active LCH, and correlate with disease risk groups.
Specific Aim 2 : Define gene expression profiles of LCH-associated circulating immature mDCs, and correlate with disease risk groups Specific Aim 3: Identify plasma proteins that impact mDC development in patients with active LCH, and correlate with disease risk groups Specific Aim 4: Test the role of LCH candidate genes on mDC development in mouse models.
Redifining Langerhans Cell Histiocytosis as a Myeloid Dysplasia and Identifying Biomarkers for Early Detection and Risk Assessment The ultimate goal of this project is to identify genes, proteins, and pathways that can be used to understand the biological basis of Langerhans Cell Histiocytosis (LCH) and to develop new strategies to diagnose, risk-stratify and cure patients with LCH. These experiments may also provide insight into normal human dendritic cell biology and identify cells and biomarkers important to diagnosis and treatment of other neoplastic hematopoietic diseases.
| Hogstad, Brandon; Berres, Marie-Luise; Chakraborty, Rikhia et al. (2018) RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med 215:319-336 |
| McClain, Kenneth L; Picarsic, Jennifer; Chakraborty, Rikhia et al. (2018) CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer 124:2607-2620 |
| Peckham-Gregory, Erin C; Chakraborty, Rikhia; Scheurer, Michael E et al. (2017) A genome-wide association study of LCH identifies a variant in SMAD6 associated with susceptibility. Blood 130:2229-2232 |
| Chakraborty, Rikhia; Hampton, Oliver A; Abhyankar, Harshal et al. (2017) Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma. Oncotarget 8:46065-46070 |
| Zinn, Daniel J; Grimes, Amanda B; Lin, Howard et al. (2016) Hydroxyurea: a new old therapy for Langerhans cell histiocytosis. Blood 128:2462-2465 |
| Chakraborty, Rikhia; Burke, Thomas M; Hampton, Oliver A et al. (2016) Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood 128:2533-2537 |
| Zinn, Daniel J; Chakraborty, Rikhia; Allen, Carl E (2016) Langerhans Cell Histiocytosis: Emerging Insights and Clinical Implications. Oncology (Williston Park) 30:122-32, 139 |
| Simko, Stephen J; McClain, Kenneth L; Allen, Carl E (2015) Up-front therapy for LCH: is it time to test an alternative to vinblastine/prednisone? Br J Haematol 169:299-301 |
| Allen, Carl E; McClain, Kenneth L (2015) Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program 2015:177-82 |
| Allen, Carl E; Ladisch, Stephan; McClain, Kenneth L (2015) How I treat Langerhans cell histiocytosis. Blood 126:26-35 |
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