Page 15 - 2019_04-Haematologica-web

Editorials
and 15q (Figure 1).11-13 Deletion of the 9p21.3 locus is the most recurrent event in BPDCN, found to be associated with a poor outcome when biallelic.11 More recently, the presence of a recurrent gene rearrangement involving the MYC locus, specifically t(6;8)(p21;q24) has been reported in several studies including one by our own group, and has been seen in association with older onset and shorter median survival.14-16 Whole-exome sequencing (WES) and targeted sequencing studies have identified recurrent mutations involving TET2, ASXL1, TP53, and NPM1,17,18 while separate studies have appointed E-box transcription factor TCF4 as a master regulator of the BPDCN onco- genic program as bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis due to disruption of the TCF4 dependent regulatory network.19 Finally, aberrant activation of the NF-kB pathway has been identified through gene expression profiling.20 However, as can be seen, our understanding of the genetic aspects of BPDCN has been somewhat limited.
In the current issue of the Journal, Sapienza et al.2 signif- icantly advance our understanding of BPDCN by analyz- ing 14 patients, as well as the patient-derived CAL-1 cell line, by WES. This broad and detailed sequencing demon- strated that BPDCN patients were affected by mutations of genes involved in epigenetic regulation, with 25 mutat- ed epigenetic modifier genes including those implicated in DNA methylation (TET2 and IDH2), chromatin accessibil- ity (ARID1a, CHD8, SMARCA1), and histone modification including: methylation (ASXL1, SUZ12, MLL), demethyla- tion (KDM4D), acetylation (EP300, EP400), ubiquitination (PHC1, PHC2), dephosphorylation (EYA2) and exchange (SRCAP) (Figure 1). This finding highlights the dysregula- tion of the epigenetic program in BPDCN as a hallmark of the disease indicating possible therapeutic interventions. In addition, by analyzing the transcriptome of the samples studied by WES, they examined the specific impact of these epigenetic-associated gene mutations. Gene set enrichment analysis additionally revealed two significant deregulation signatures associated with methylation of DNA: one driven by KDM5B34 histone demethylase and another by the PRMT5 methyltransferase-associated gene. The authors also detected gene set enrichment of those genes associated with response to decitabine, a DNA demethylating agent. Finally, based on the apparent signif- icance of epigenetics in BPDCN, the authors did what few have done before, and tested in vivo the efficacy of four US Food and Drug Administration (FDA)-approved epigenetic drugs (5’-Azacytidine, decitabine, romidepsin and borte- zomib) in a mouse xenograft model using the CAL-1 cell line. These drugs were used as single agents or in combi- nation, and when used as a single agent, 5’-Azacytidine and decitabine significantly prolonged mice overall sur- vival, while among all the combinations tested, treatment with 5’-Azacytidine in combination with decitabine achieved the best result in terms of survival. The signifi- cance of this study cannot be understated as it links geno- type to advancements in epigenetic forms of treatment and fundamental biological processes.
Blastic plasmacytoid dendritic cell neoplasm is a rare dis- ease with an extremely aggressive behavior; the advances here in the genetics and molecular aspects of this entity, as well as the therapeutic approach, are quite revealing and
significantly open the door for future clinical trials. This work nicely provides further support for the essence of why development of new epigenetic treatment strategies are a rational approach for this aggressive disease.
References
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