Vitamin A and MITF regulation in disease progression of patients with Lymphangioleiomyomatosis (LAM)

Authors

• G Pacheco-Rodriguez
• WK Steagall
• JC Valencia
• M Stylianou
• M Uhart
• J Moss

Abstract

Lymphangioleiomyomatosis (LAM) is a destructive metastatic lung disease characterized by the proliferation of smooth muscle-like LAM cells with mutated Tuberous Sclerosis Complex (TSC) genes TSC1 and TSC2. LAM occurs sporadically or as part of an inherited disorder, TSC. LAM patients also present with circulating cells with loss of heterozygosity (LOH) of the TSC genes. LAM cells are found in lung nodules, which contain spindle-shaped LAM cells (undifferentiated cells) and epithelioid LAM cells (fully differentiated cells). The latter cells contain melanosome-like structures identified with monoclonal antibody HMB-45, which recognizes the gene product of Pmel17 (gp100), which is regulated by MITF (microphtalmia transcription factor). Thus, we investigated the regulation of the abnormal expression of melanogenic proteins in lung LAM cells. MITF-A and H were found in both microdissected LAM lung nodules and cultured LAM cells. A subpopulation of circulating tumor cells expressed MITF and exhibited TSC2LOH. Retinoic acid and its metabolites regulate MITF expression and increased proliferation of lung LAM cells. Furthermore, in LAM patients higher blood levels of vitamin A were associated with higher percent-predicted FEV1 and DLCO (all P<0.001) in a multivariate analysis adjusting for initial pulmonary function values, TSC status, mTOR inhibitor treatment, and time of visit in 653 LAM patients over 4502 visits. The yearly rate of decline of percent-predicted FEV1 was slower for those with higher vitamin A levels as compared to those with lower levels (P=0.003). Our data suggest that retinoic acid metabolism could play a role in LAM lung disease progression.

Scientific Focus Area: Clinical Research

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