Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome.

This corrects the article DOI: 10.1038/leu.2016.276.

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes.

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

IRAK signalling in cancer.

Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-κB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development.

EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk.

In an effort to identify novel biallelically inactivated tumor suppressor genes (TSGs) in sporadic invasive and preinvasive non-small-cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multiple 'omics' approach to investigate patient-matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes and in the earliest stages of lung cancer. We found that decreased EYA4 expression is not only associated with poor survival in sporadic lung cancers but also that EYA4 single-nucleotide polymorphisms are associated with increased familial cancer risk, consistent with EYA4s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we found that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross-examination of EYA4 expression across multiple tumor types suggests a cell-type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC.

Deregulation of microRNAs in myelodysplastic syndrome.

Myelodysplastic syndromes (MDSs) consist of a family of hematopoietic stem cell (HSC) disorders characterized by ineffective differentiation of hematopoietic progenitors, bone marrow dysplasia, genetic instability and a propensity to develop acute myeloid leukemia. The development of MDS is poorly understood and therefore, effective treatment options are limited. Recent progress has been made in identifying altered signaling pathways and understanding the HSC defects, which are thought to contribute to the pathogenesis of MDS. Several of these findings have implicated aberrant expression and function of microRNAs (miRNAs). Unique miRNA expression patterns have been identified in MDS patients and modeled in mice to recapitulate features of MDS. Here, we review miRNA expression profiles identified in MDS patients, and describe the association of miRNA expression with MDS subtypes and disease outcome, clinical implications of miRNAs in MDS and deregulation of miRNAs in mouse model systems of MDS.

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity.

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.