title: Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis.
abstract: The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target.
authors.affiliation: Department of Medicine, Surgery, and Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA. jmd12@columbia.edu
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Kazushi
authors.initials: K
authors.lastname: Imai
authors.forename: John
authors.initials: J
authors.lastname: Schiltz
authors.forename: Natalya
authors.initials: N
authors.lastname: Kolesnekova
authors.forename: David
authors.initials: D
authors.lastname: Sternberg
authors.forename: Kathleen
authors.initials: K
authors.lastname: Benson
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Theresa
authors.initials: T
authors.lastname: Smolarek
authors.forename: Murty
authors.initials: M
authors.lastname: Vundavalli
authors.forename: Joshua
authors.initials: J
authors.lastname: Sonnet
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Kiran
authors.initials: K
authors.lastname: Chada
mesh_terms: D000818:Animals; D005260:Female; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism
chemical_list: D025743:HMGA2 Protein