Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).

• MeSH
• chromozomální delece * MeSH
• dítě MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy, pár 7 genetika   MeSH
• monozomie MeSH
• myelodysplastické syndromy * diagnóza   genetika   terapie   MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• spontánní remise MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• SAMD9 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

• MeSH
• alografty MeSH
• homologní transplantace MeSH
• juvenilní myelomonocytární leukemie * MeSH
• lidé MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50-60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.

• MeSH
• dítě MeSH
• genový knockdown MeSH
• juvenilní myelomonocytární leukemie krev   farmakoterapie   genetika   patologie   MeSH
• kojenec MeSH
• kostní dřeň patologie   MeSH
• leukocyty mononukleární MeSH
• lidé MeSH
• mladiství MeSH
• nádorové buňky kultivované MeSH
• předškolní dítě MeSH
• primární buněčná kultura MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• RNA dlouhá nekódující antagonisté a inhibitory   genetika   metabolismus   MeSH
• sekvenování transkriptomu MeSH
• studie případů a kontrol MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové látky MeSH
• RNA dlouhá nekódující MeSH

Disease progression in myelodysplastic syndromes (MDS) and myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is a major source of mortality. The European Bone Marrow Working Group organized a dedicated workshop to address MDS and MDS/MPN progression, and myeloid neoplasms with histiocytic and lymphoblastic outgrowths in 2019 in Frankfurt, Germany. In this report, we summarize clinical, histopathological, and molecular features of 28 cases. Most cases illustrate that prognostic mutational profiles change during follow-up due to accumulation of high-risk mutations in the trunk clone, and that results from repeated molecular testing can often explain the clinical progression, suggesting that regular genetic testing may predict transformation by early detection of aggressive clones. Importantly, identical mutations can be linked to different clinical behaviors or risks of fibrotic progression and/or transformation in a context-dependent manner, i.e., MDS or MDS/MPN. Moreover, the order of mutational acquisition and the involved cell lineages matter. Several cases exemplify that histiocytic outgrowths in myeloid neoplasms are usually accompanied by a more aggressive clinical course and may be considered harbinger of disease progression. Exceptionally, lymphoblastic transformations can be seen. As best estimable, the histiocytic and lymphoblastic compounds in all occasions were clonally related to the myeloid compound and-where studied-displayed genomic alterations of, e.g., transcription factor genes or genes involved in MAPK signaling that might be mechanistically linked to the respective type of non-myeloid outgrowth.

• Klíčová slova
• Histiocytic transformation, Lymphoblastic, MDS, MDS/MPN, Mutations, Myeloid neoplasm, Progression, Transformation,
• MeSH
• dospělí MeSH
• kostní dřeň patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• myelodysplastické syndromy genetika   patologie   MeSH
• myelodysplasticko-myeloproliferativní nemoci genetika   patologie   MeSH
• nádorová transformace buněk genetika   patologie   MeSH
• progrese nemoci * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výchova a vzdělávání metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Evropa MeSH
• Německo MeSH

Juvenile myelomonocytic leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a "discovery cohort" comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.

• Klíčová slova
• CircRNAs, RNA-Seq, juvenile myelomonocytic leukemia, microRNAs, regulatory networks,
• Publikační typ
• časopisecké články MeSH

• MeSH
• dítě MeSH
• juvenilní myelomonocytární leukemie genetika   metabolismus   patologie   MeSH
• lidé MeSH
• předškolní dítě MeSH
• regulace genové exprese u leukemie * MeSH
• RNA dlouhá nekódující biosyntéza   genetika   MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• RNA dlouhá nekódující MeSH
• RNA nádorová MeSH

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

• MeSH
• biopsie MeSH
• chromatin genetika   metabolismus   MeSH
• dítě MeSH
• DNA-(cytosin-5-)methyltransferasa metabolismus   MeSH
• DNA-(cytosin-5)-methyltransferasa 1 metabolismus   MeSH
• DNA-methyltransferasa 3B MeSH
• epigenomika MeSH
• juvenilní myelomonocytární leukemie genetika   mortalita   patologie   terapie   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA * MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• Noonanové syndrom genetika   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• prospektivní studie MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-cbl MeSH
• protoonkogenní proteiny p21(ras) genetika   metabolismus   MeSH
• regulace genové exprese u leukemie MeSH
• signální transdukce genetika   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   metabolismus   MeSH
• upregulace MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH
• DNA-(cytosin-5-)methyltransferasa MeSH
• DNA-(cytosin-5)-methyltransferasa 1 MeSH
• DNMT1 protein, human MeSH Prohlížeč
• KRAS protein, human MeSH Prohlížeč
• protinádorové látky MeSH
• protoonkogenní proteiny c-cbl MeSH
• protoonkogenní proteiny p21(ras) MeSH
• PTPN11 protein, human MeSH Prohlížeč
• tyrosinfosfatasa nereceptorového typu 11 MeSH