Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- myelodysplastické syndromy * genetika klasifikace patologie MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- variabilita počtu kopií segmentů DNA MeSH
- ztráta heterozygozity MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace * MeSH
- myelodysplastické syndromy * genetika diagnóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ubikvitin aktivující enzymy * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
VEXAS syndrom (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) je vzácné autoinflamatorní onemocnění, způsobené somatickou mutací v genu UBA1 v hematopoetických progenitorových buňkách, které postihuje dospělé pacienty ve vyšším věku. Onemocnění se projevuje systémovými příznaky (horečky, únava), zánětlivými projevy na kůži, v oblasti očí, postižením plic, cév a chrupavek s přidruženými hematologickými symptomy, jako jsou makrocytární anémie, trombocytopenie a přítomnost vakuol v myeloidních a erytroidních prekurzorech. Zároveň je spojené se zvýšeným rizikem rozvoje maligního hematologického onemocnění. Většina pacientů je refrakterních vůči běžné protizánětlivé a imunosupresivní léčbě. Záněty a selhávání kostní dřeně často postupně vedou k závažným zdravotním komplikacím a významné mortalitě. V současné chvíli neexistuje efektivní standardizovaná léčba. Pro určitou skupinu nemocných je vhodnou terapií transplantace krvetvorných kmenových buněk, která může být kurativní. Dalšími možnostmi léčby mohou být hypometylační látky či léčiva cílící na dráhy cytokinů a zánětlivé odpovědi. Společně se souhrnnou informací o VEXAS syndromu zde prezentujeme dvě kazuistiky pacientů, u nichž jsme na našem pracovišti detekovali mutace v genu UBA1.
VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a rare autoinflammatory late-onset disease caused by the UBA1 gene somatic mutation in haematopoietic progenitor cells. In patients, we can observe systemic symptoms (fever and fatigue), inflammatory manifestations on the skin, in the eye area, and involvement of the lungs, blood vessels, and cartilage with associated haematological symptoms such as macrocytic anaemia, thrombocytopenia, and presence of vacuoles in myeloid and erythroid precursors. In most cases, patients are refractory to common anti-inflammatory and immunosuppressive treatments and have a higher risk of developing haematological malignancies. Subsequently, inflammation and bone marrow failure often lead to severe morbidity and significant mortality. Currently, there is no effective standardized therapy. Haematopoietic stem cell transplantation may be a suitable treatment for a specific group of patients. Hypomethylating agents and/or drugs targeting cytokine and inflammatory response pathways appear to be other therapeutic options. Together with an overview of VEXAS syndrome, we present two case reports of patients with the UBA1 mutations detected in our laboratory.
- Klíčová slova
- syndrom VEXAS, gen UBA1,
- MeSH
- diferenciální diagnóza MeSH
- genetické nemoci vázané na chromozom X * diagnóza farmakoterapie genetika klasifikace MeSH
- hematopoetické kmenové buňky patologie MeSH
- kazuistiky jako téma MeSH
- lidé MeSH
- mutace genetika MeSH
- myelodysplastické syndromy diagnóza klasifikace patologie MeSH
- senioři MeSH
- vakuoly patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
VEXAS syndrom je v roce 2020 nově rozpoznaná a popsaná autoinflamatorní choroba. Akronym VEXAS je složen z prvních písmen V = vakuoly, E = E1 enzymy, X = X-chromozom, A = autoinflamatorní, S = somatické. Podstatou onemocnění je získaná somatická patogenní varianta v genu UBA1. Tento gen kóduje enzym E1, který je zodpovědný za regulaci zánětlivých proteinů vazbou na ubikvitin (ubikvitinizace). Kvůli uložení genu na X chromozomu toto onemocnění postihuje muže, a to v jejich druhé polovině života. Choroba má pestré inflamatorní projevy s hematologickými (hyperkoagulace, anémie, trombocytopenie), dermatologickými (Sweetův snydrom) a revmatologickými (perichondritis, artritis) symptomy. Tyto příznaky lze shrnout do pracovní diagnózy „nespecifikovaná systémová autoinflamatorní choroba“ (undifferentiated systemic autoinflammatory disorder – USAID). Průkaz vakuol při cytologickém hodnocení kostní dřeně je pro tuto chorobu charakteristický a definitivní diagnózu potvrzuje průkaz defektu UBA1 genu. V textu popisujeme našeho prvního pacienta s VEXAS syndromem a uvádíme stručný přehled literatury.
The VEXAS syndrome is a recently identified autoinflammatory systemic disease. The acronym VEXAS stands for Vacuoles, E1 enzyme, X linked, Autoinflammatory, Somatic. The disease is due to an acquired somatic mutation of the UBA1 gene, which encodes for the E 1 enzyme, which in turn is responsible for the ubiquitination of proteins. Due to its location on the X chromosome, the disease predominantly affects men in the second half of life. The patients present with a plenty of inflammatory clinical symptoms, often with overlap of hematologic (anemia, thrombocytopenia hypercoagulation), dermatologic (Sweet syndrom), and rheumatologic (artritis, perichondritis) symptoms. These symptoms can be assessed as “undifferentiated systemic autoinflammatory disorder (USAID) ”. Bone marrow smear with the presence of cytoplasmic vacuoles in the bone marrow is characteristic and the mutation of UBA1 gene is proof of this diagnosis. In this article, we report our first clinical case of a VEXAS syndrome and give an overview of the literature, including pathophysiology, clinical symptoms and diagnostics of the disease.
- Klíčová slova
- syndrom VEXAS,
- MeSH
- diferenciální diagnóza MeSH
- genetické nemoci vázané na chromozom X * diagnóza farmakoterapie genetika klasifikace MeSH
- kožní manifestace MeSH
- lidé MeSH
- myelodysplastické syndromy diagnóza klasifikace MeSH
- příznaky a symptomy MeSH
- senioři MeSH
- Sweetův syndrom diagnóza etiologie MeSH
- vakuoly patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
Patients with myelodysplastic neoplasms (MDS) are classified according to the risk of acute myeloid leukemia transformation. Some lower-risk MDS patients (LR-MDS) progress rapidly despite expected good prognosis. Using diagnostic samples, we aimed to uncover the mechanisms of this accelerated progression at the transcriptome level. RNAseq was performed on CD34+ ribodepleted RNA samples from 53 LR-MDS patients without accelerated progression (stMDS) and 8 who progressed within 20 months (prMDS); 845 genes were differentially expressed (ІlogFCІ > 1, FDR < 0.01) between these groups. stMDS CD34+ cells exhibited transcriptional signatures of actively cycling, megakaryocyte/erythrocyte lineage-primed progenitors, with upregulation of cell cycle checkpoints and stress pathways, which presumably form a tumor-suppressing barrier. Conversely, cell cycle, DNA damage response (DDR) and energy metabolism-related pathways were downregulated in prMDS samples, whereas cell adhesion processes were upregulated. Also, prMDS samples showed high levels of aberrant splicing and global lncRNA expression that may contribute to the attenuation of DDR pathways. We observed overexpression of multiple oncogenes and diminished differentiation in prMDS; the expression of ZEB1 and NEK3, genes not previously associated with MDS prognosis, might serve as potential biomarkers for LR-MDS progression. Our 19-gene DDR signature showed a significant predictive power for LR-MDS progression. In validation samples (stMDS = 3, prMDS = 4), the key markers and signatures retained their significance. Collectively, accelerated progression of LR-MDS appears to be associated with transcriptome patterns of a quiescent-like cell state, reduced lineage differentiation and suppressed DDR, inherent to CD34+ cells. The attenuation of DDR-related gene-expression signature may refine risk assessment in LR-MDS patients.
- MeSH
- buněčná adheze MeSH
- buněčný cyklus MeSH
- kinasy NEK genetika metabolismus MeSH
- lidé MeSH
- myelodysplastické syndromy * genetika MeSH
- nádory * MeSH
- oprava DNA MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: To date, no chemoresistance predictors are included in acute myeloid leukaemia (AML) prognostic scoring systems to distinguish responding and refractory AML patients prior to chemotherapy. ABC transporters have been described as altering AML chemosensitivity; however, a relevant study investigating their role at various molecular levels was lacking. METHODS: Gene expression, genetic variants, methylation and activity of ABCA2, ABCA5, ABCB1, ABCB6, ABCC1, ABCC3 and ABCG2 were analysed in AML blasts and healthy myeloblasts. Differences between responding and refractory AML in a cohort of 113 patients treated with 3 + 7 induction therapy were explored. RESULTS: ABCC3 variant rs2301837 (p = 0.049), ABCG2 variant rs11736552 (p = 0.044), higher ABCA2 (p = 0.021), ABCC1 (p = 0.017), and ABCG2 expression (p = 0.023) and a higher number of concurrently overexpressed transporters (p = 0.002) were predictive of treatment failure by multivariate analysis. Expression of ABCA5 (p = 0.003), ABCB6 (p = 0.001) and ABCC3 (p < 0.0001) increased significantly after chemotherapy. Higher ABCG2 promoter methylation correlated with lower ABCG2 expression (p = 0.0001). ABCC1 was identified as the most active transporter in AML blasts by functional analysis. CONCLUSIONS: ABC transporters, especially ABCC1 seem to contribute substantially to AML chemoresistance. A detailed understanding of chemoresistance mechanisms and the clinical implications of chemosensitivity predictors may lead to alternative therapeutic approaches for AML patients with unveiled chemoresistance signatures.
- MeSH
- ABC transportéry * metabolismus MeSH
- akutní myeloidní leukemie * farmakoterapie genetika MeSH
- chemorezistence genetika MeSH
- lidé MeSH
- terapie neúspěšná MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.
Východiska: Hypoplastická forma myelodysplastické neoplazie (MDS-h) je vzácná porucha krvetvorby charakterizována periferní cytopenií, hypoplazií (celularita ≤ 25 %) a dysplastickými změnami v kostní dřeni. Ve srovnání s normo-/hypercelulárním MDS je kromě hypocelularity u pacientů s MDS-h nalézána těžší neutropenie a trombocytopenie, nižší procento blastů a méně častěji abnormální karyotyp. Při diferenciální diagnóze je obtížné odlišit především MDS-h od aplastické anemie. Abnormální karyotyp je nalézán u 15–50 % pacientů s MDS-h a mezi nejběžnější chromozomální aberace patří −5/del (5q), −7/del (7q), +8, 17pLOH, del (20q), UPD v 4q, 11q, 13q, 14q. Přibližně 35 % pacientů s MDS-h nese somatické mutace, které jsou nejčastěji detekovány v genech PIGA, TET2, DNMT3A, RUNX1, NPM1, ASXL1, STAG2, APC. V patofyziologii MDS-h hraje klíčovou roli defektní imunitní odpověď, při které dochází k poškození hematopoetických kmenových buněk (hematopoietic stem cells – HSC) nebo progenitorových buněk (hematopoietic progenitor cells – HPC) abnormálně aktivovanými T buňkami. Expandované T buňky produkují nadměrné množství prozánětlivých cytokinů (IFN- g a TNF-a), které inhibují proliferaci HSC/HPC a indukují jejich apoptózu. Antigeny spouštějící abnormální imunitní odpověď nejsou známy, ale mezi potenciální kandidáty patří protein WT1 a molekuly HLA I. třídy. MDS-h nepředstavuje fenotypově homogenní podskupinu MDS, ale spíše jde o smíšenou entitu zahrnující jak pacienty vykazující znaky podobné myeloidní neoplazii, tak pacienty se znaky nemaligního útlumu kostní dřeně. Právě stanovení převažujícího fenotypu u MDS-h je důležité pro zvolení optimální léčby a predikci prognózy. Cíl: Cílem tohoto sdělení je poukázat na zajímavou hypoplastickou formu MDS, jejíž diagnostika je obtížná, a přehledně popsat její hlavní klinicko-patologické znaky, genetické pozadí a mechanizmy abnormální imunitní odpovědi.
Background: Hypoplastic myelodysplastic neoplasm (MDS-h) is a rare hematopoietic disorder characterized by peripheral cytopenia, hypoplasia (cellularity ≤ 25%) and dysplastic changes in the bone marrow. Compared to normo- /hypercellular MDS, in addition to hypocellularity, MDS-h patients have more profound neutropenia and thrombocytopenia, a lower percentage of blasts, and less frequent abnormal karyotype. It is difficult to distinguish MDS-h from aplastic anemia in differential diagnosis. Abnormal karyotype is found in 15–50% of MDS-h patients and the most common chromosomal aberrations include −5/del (5q), −7/del (7q), +8, 17pLOH, del (20q), UPD at 4q, 11q, 13q, and 14q. Approximately 35% of MDS-h patients harbour somatic mutations that are most often detected in PIGA, TET2, DNMT3A, RUNX1, NPM1, ASXL1, STAG2, and APC genes. An autoimmune destruction of hematopoietic stem cells (HSCs) or hematopoietic progenitor cells (HPCs) mediated by abnormally activated T cells plays a key role in the pathophysiology of MDS-h. Expanded T cells overproduce proinflammatory cytokines (IFN- g and TNF-a), which inhibit proliferation and induce apoptosis of HSC/HPCs. The antigens that trigger the immune response are not known, but potential candidates have been suggested such as WT1 protein and HLA class I molecules. MDS-h does not represent a phenotypically homogeneous subtype of MDS, but rather it is a mixed entity comprising both patients showing features similar to myelodysplastic neoplasm and patients with features of non-malignant bone marrow failure. Determining the prevailing phenotype in MDS-h is important for choosing the optimal treatment and prognosis prediction. Purpose: The aim of this article is to point out an interesting hypoplastic MDS, the diagnosis of which is difficult, and to provide an overview of its main clinical-pathological features, genetic background, and mechanisms of aberrant immune response.
- MeSH
- aplastická anemie * genetika patofyziologie MeSH
- lidé MeSH
- myelodysplastické syndromy * genetika patofyziologie MeSH
- syndromy selhání kostní dřeně MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
