MDS is a complex disease with a fascinating origin. A plethora of molecular pathway disruptions have been postulated to explain the heterogeneity of the disease phenotype, but no exclusive genetic drivers are capable of recapitulating all its aspects, wrote the researchers, noting the heterogeneity of MDS introduces challenges when trying to fully understand the pathogenesis of the group of disorders.

They added, Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis.

Recently, a gene expression-based classification was applied to RNA-sequencing data from CD34+ cells of 100 patients with MDS, resulting in the identification of 2 subcellular populations. The populations were associated and characterized by increased expression of genes related to erythroid/megakaryocytic lineages and those related to immature progenitor cells.

In addition, several genes in the iron pathway have been implicated in the pathogenesis of MDS, including:

Other recent research involved identifying differences in downstream pathways, particularly for genes of the spliceosomal complex, with all studies showing convergent functions in the 3 splice site. Some studies have shown that splicing factor mutations could result in the build-up of R-loops, including one that showed an increase in R-loops in an induced pluripotent stem cell clone harboring a SF3B1 mutation compared with a clone lacking SF3B1 mutations from a patient with MDS.

For patients with an SF3B1 mutation, luspatercept has been shown to improve response in low-grade MDS through its ability to increase erythroid maturation and hemoglobin levels.

More recently, splicing factor mutations were found to lead to the activation of inflammation and innate immunity pathways (e.g., NF-kB) or indirectly by deregulating histone acetylase (e.g., sirtuins), detailed the researchers. In fact, sirtuin 1 (SIRT1) was found to be involved in HSPC maintenance. U2AF1 mutant patients had IRAK4, a serine/threonine that activates NF-kB in the Toll-like receptor and T-cell receptor signaling pathways, that is aberrantly spliced.

Treatments targeting splicing factor mutations have mainly included developing pan-splicing modulators, including bacterially derived products and analogs that have been shown to bind the SF3B complex and disrupt spliceosome assembly.

Research focused on novel treatments for mutant p53 has also found that PRIMA-1Met, an investigational small molecule, restores the conformation of p53 and rescues p53 function. Another treatment, APR-246, has shown promise either as monotherapy or in combination with 5-azacitidine in reactivating p53 and inducing apoptosis in MDS cases carrying TP53 mutations.

Reference: Awada H, Thapa B, and Visconte V. The genomics of myelodysplastic syndrome: origins of disease evolution, biological pathways, and prognostic implications. Cells.2020;9(11):2512. doi:10.3390/cells9112512

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