Sirolimus-related anal ulceration in a female patient after allogeneic stem cell transplantation

Haik, Laura; Beylot‐Barry, M.; Vigouroux, Stéphane; Tabrizi, Reza; Milpied, Noël

doi:10.1038/bmt.2015.198

Cited by 2 publications

(1 citation statement)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33 Interestingly, although even high rapamycin concentrations are not cytotoxic for most cell types, a significant number of patients treated with rapamycin for graft-versus-host disease suffer from chronic ulcers. 34,35 It is conceivable that these ulcerations are driven by similar pathways as in BU.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR

et al. 2017

View full text Add to dashboard Cite

Mycolactone, the macrolide exotoxin produced by Mycobacterium ulcerans, is central to the pathogenesis of the chronic necrotizing skin disease Buruli ulcer (BU). Here we show that mycolactone acts as an inhibitor of the mechanistic Target of Rapamycin (mTOR) signaling pathway by interfering with the assembly of the two distinct mTOR protein complexes mTORC1 and mTORC2, which regulate different cellular processes. Inhibition of the assembly of the rictor containing mTORC2 complex by mycolactone prevents phosphorylation of the serine/threonine protein kinase Akt. The associated inactivation of Akt leads to the dephosphorylation and activation of the Akt-targeted transcription factor FoxO3. Subsequent up-regulation of the FoxO3 target gene BCL2L11 (Bim) increases expression of the pro-apoptotic regulator Bim, driving mycolactone treated mammalian cells into apoptosis. The central role of Bim-dependent apoptosis in BU pathogenesis deduced from our experiments with cultured mammalian cells was further verified in an experimental M. ulcerans infection model. As predicted by the model, M. ulcerans infected Bim knockout mice did not develop necrotic BU lesions with large clusters of extracellular bacteria, but were able to contain the mycobacterial multiplication. Our findings provide a new coherent and comprehensive concept of BU pathogenesis.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%