Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis.
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.
D'Armiento
Jeanine
J
Department of Medicine, Surgery, and Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA. jmd12@columbia.edu
Imai
Kazushi
K
Schiltz
John
J
Kolesnekova
Natalya
N
Sternberg
David
D
Benson
Kathleen
K
Pardo
Annie
A
Selman
Moises
M
Smolarek
Theresa
T
Vundavalli
Murty
M
Sonnet
Joshua
J
Szabolcs
Matthias
M
Chada
Kiran
K
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
D025743:HMGA2 Protein