Vulvar Langerhans cell histiocytosis: Clinicopathologic characteristics, mutational profile, and treatment of 4 patients in a single-center cohort

Renier, Ruben; Haes, Petra De; Bosisio, Francesca Maria; Bempt, Isabelle Vanden; Woei-A-Jin, F.J. Sherida H.

doi:10.1016/j.jdcr.2023.03.024

JAAD Case Reports

2023

DOI: 10.1016/j.jdcr.2023.03.024

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Vulvar Langerhans cell histiocytosis: Clinicopathologic characteristics, mutational profile, and treatment of 4 patients in a single-center cohort

Ruben Renier¹,

Petra De Haes²,

Francesca Maria Bosisio³

et al.

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Cited by 2 publications

References 9 publications

(19 reference statements)

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Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

Kemps,

Woei-A-Jin,

Schöffski

et al. 2024

Blood Neoplasia

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Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

Kemps,

Woei-A-Jin,

Schöffski

et al. 2024

Blood Neoplasia

View full text Add to dashboard Cite

BRAF ^Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

Lauinger,

Christen,

Klar

et al. 2023

Sci. Adv.

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In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF Δβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF Δβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF ΔLNVTAP>F and two novel mutants, BRAF delinsFS and BRAF ΔLNVT>F , and compare them with other BRAF Δβ3-αC oncoproteins. We show that BRAF Δβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF Δβ3-αC oncoproteins, e.g., BRAF ΔLNVTAP>F , increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF Δβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.

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Vulvar Langerhans cell histiocytosis: Clinicopathologic characteristics, mutational profile, and treatment of 4 patients in a single-center cohort

Cited by 2 publications

References 9 publications

Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

BRAF ^Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

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Vulvar Langerhans cell histiocytosis: Clinicopathologic characteristics, mutational profile, and treatment of 4 patients in a single-center cohort

Cited by 2 publications

References 9 publications

Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

Contact Info

Product

Resources

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BRAF ^Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability