Hypoplastic myelodysplastic syndrome (hMDS) and aplastic anemia (AA) are rare hematopoietic disorders characterized by pancytopenia with hypoplastic bone marrow (BM). hMDS and idiopathic AA share overlapping clinicopathological features, making a diagnosis very difficult. The differential diagnosis is mainly based on the presence of dysgranulopoiesis, dysmegakaryocytopoiesis, an increased percentage of blasts, and abnormal karyotype, all favouring the diagnosis of hMDS. An accurate diagnosis has important clinical implications, as the prognosis and treatment can be quite different for these diseases. Patients with hMDS have a greater risk of neoplastic progression, a shorter survival time and a lower response to immunosuppressive therapy compared with patients with AA. There is compelling evidence that these distinct clinical entities share a common pathophysiology based on the damage of hematopoietic stem and progenitor cells (HSPCs) by cytotoxic T cells. Expanded T cells overproduce proinflammatory cytokines (interferon‑γ and tumor necrosis factor‑α), resulting in decreased proliferation and increased apoptosis of HSPCs. The antigens that trigger this abnormal immune response are not known, but potential candidates have been suggested, including Wilms tumor protein 1 and human leukocyte antigen class I molecules. Our understanding of the molecular pathogenesis of these BM failure syndromes has been improved by next‑generation sequencing, which has enabled the identification of a large spectrum of mutations. It has also brought new challenges, such as the interpretation of variants of uncertain significance and clonal hematopoiesis of indeterminate potential. The present review discusses the main clinicopathological differences between hMDS and acquired AA, focuses on the molecular background and highlights the importance of molecular testing.

• Klíčová slova
• acquired aplastic anemia, dysregulated non‑coding RNAs, hypoplastic myelodysplastic syndrome, immunopathogenesis, mutational landscape,
• MeSH
• autoimunitní hemolytická anemie etiologie   genetika   MeSH
• imunita genetika   imunologie   MeSH
• lidé MeSH
• myelodysplasticko-myeloproliferativní nemoci etiologie   genetika   MeSH
• prognóza MeSH
• syndromy selhání kostní dřeně etiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The DLK1⁻DIO3 region contains a large miRNA cluster, the overexpression of which has previously been associated with myelodysplastic syndromes (MDS). To reveal whether this overexpression is epigenetically regulated, we performed an integrative analysis of miRNA/mRNA expression and DNA methylation of the regulatory sequences in the region (promoter of the MEG3 gene) in CD34+ bone marrow cells from the patients with higher-risk MDS and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), before and during hypomethylating therapy with azacytidine (AZA). Before treatment, 50% of patients showed significant miRNA/mRNA overexpression in conjunction with a diagnosis of AML-MRC. Importantly, increased level of MEG3 was associated with poor outcome. After AZA treatment, the expression levels were reduced and were closer to those seen in the healthy controls. In half of the patients, we observed significant hypermethylation in a region preceding the MEG3 gene that negatively correlated with expression. Interestingly, this hypermethylation (when found before treatment) was associated with longer progression-free survival after therapy initiation. However, neither expression nor methylation status were associated with future responsiveness to AZA treatment. In conclusion, we correlated expression and methylation changes in the DLK1⁻DIO3 region, and we propose a complex model for regulation of this region in myelodysplasia.

• Klíčová slova
• 14q32, MEG3, acute myeloid leukemia, azacitidine, microRNA, myelodysplastic syndromes,
• Publikační typ
• časopisecké články MeSH

Meningiomas represent one of the most common types of primary intracranial tumours. However, the specific molecular mechanisms underlying their pathogenesis remain uncertain. Loss of chromosomes 22q, 1p, and 14q have been implicated in most meningiomas. Inactivation of the NF2 gene at 22q12 has been identified as an early event in their pathogenesis, whereas abnormalities of chromosome 14 have been reported in higher-grade as well as recurrent tumours. It has long been supposed that chromosome 14q32 contains a tumour suppressor gene. However, the identity of the potential 14q32 tumour suppressor remained elusive until the Maternally Expressed Gene 3 (MEG3) was recently suggested as an ideal candidate. MEG3 is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA). In meningiomas, loss of MEG3 expression, its genomic DNA deletion and degree of promoter methylation have been found to be associated with aggressive tumour growth. These findings indicate that MEG3 may have a significant role as a novel long noncoding RNA tumour suppressor in meningiomas.

• MeSH
• lidé MeSH
• lidské chromozomy, pár 14 genetika   MeSH
• meningeom genetika   MeSH
• nádory mozku genetika   MeSH
• patologická angiogeneze genetika   MeSH
• RNA dlouhá nekódující genetika   MeSH
• signální transdukce genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• MEG3 non-coding RNA, human MeSH Prohlížeč
• RNA dlouhá nekódující MeSH