A boost for eltrombopag

This is the authors' abstract. We don't add key points for this paper.

The first is common to all BMF syndromes.The growth defects induce pressure for growth of clones that underwent genomic adaptation.Indeed, in several patients described by the authors, copy number-neutral loss of heterozygosity led to correction of the ERG haploinsufficiency and, consequently, correction of the BMF.This correction also directly proves the functional role of ERG haploinsufficiency in the syndrome.Yet genomic corrections can often be maladaptive.Growthpromoting mutations in other genes may cause expansion of hematopoietic clones and cause HM.Indeed, in 1 of the patients, still with BMF without HM, the authors discovered a subclone with pathogenic RUNX1 mutation.This clone may eventually evolve into HM.The second potential mechanism is an indirect HM-promoting effect of the mutated ERG.Interestingly, all the pathogenic or likely pathogenic mutations were point mutations in or at the vicinity of the ETS domain, thus retaining the amino terminal part of ERG.The mutated protein was expressed.Similar somatic mutations were noted by the authors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database, suggesting a potential active role of mutated ERG in cancer.It is possible that the interaction between the mutated ERG with other "heptad" hematopoietic TFs could contribute to development of HM. 7 We discovered that ERG interaction (through proline #199) with the NCOR/HDAC3 repressor complex is necessary for its leukemogenic activity.8 Almost all mutated ERG described in the current publication retain this interaction.

Highlights the mechanisms by which ERG haploinsufficiency and subsequent genomic adaptations contribute to bone marrow failure and the risk of hematopoietic malignancies.