The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms

Histiocytic neoplasms are a rare group of diseases with significant morbidity due to histiocytic infiltration to critical organ systems, impeding their normal functions.Diagnosis is based on the identification of CD68+ histiocyte infiltration within tissues, demonstrating varied expression of dendritic and monocytic lineage cells depending on the type of histiocytosis [1,2].The predominant histiocytoses are Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman-Destombes (RDD) disease.The pathogenesis of histiocytic neoplasms is driven by inflammation [1] and mutations mainly activating the MAPK/ERK [3] and PI3K pathways [1,3,4], but little is known about the epigenetic landscape involved in these neoplasms.Epigenetic changes, such as DNA methylation, are critical for mammalian development and are frequently implicated in oncogenesis.The process of DNA methylation involves DNA methyltransferases (DNMTs) catalyzing the transfer of a methyl group to a cytosine residue, resulting in the formation of 5-methylcytosine within a CpG dinucleotide.Regions enriched in CpG, called CpG islands, are commonly found in the promoters of genes.In cancer, aberrant hypermethylation of CpG islands is strongly associated with gene silencing, contributing to the inactivation of tumor suppressor genes [5].Epigenetic changes are potentially reversible by pharmacological inhibition of DNA methylation and histone deacetylation, thus providing a promising target for therapeutic intervention.Given that histiocytic neoplasms have predominantly been analyzed for DNA mutations, profiling their methylome can enhance our understanding of disease pathogenesis.Moreover, pharmacological inhibition of BRAF and MEK has shown clinical promise in histiocytic neoplasms; however, their clinical applicability is limited due to toxicity profile, side effects and documented resistance [6,7].Therefore, identifying new therapeutic targets is needed for these patients.