Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

• MeSH
• dítě MeSH
• dyskeratosis congenita * genetika   MeSH
• lidé MeSH
• mutace MeSH
• proteiny vázající telomery * genetika   metabolismus   MeSH
• shelterinový komplex MeSH
• telomery * genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• antilymfocytární sérum * terapeutické užití   MeSH
• aplastická anemie * farmakoterapie   MeSH
• cyklosporin * terapeutické užití   MeSH
• dítě MeSH
• imunosupresiva * terapeutické užití   MeSH
• kojenec MeSH
• koně MeSH
• králíci MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• králíci MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• dopisy MeSH
• srovnávací studie MeSH

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

Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

• MeSH
• akutní myeloidní leukemie * MeSH
• blastická krize terapie   MeSH
• chronická myeloidní leukemie * farmakoterapie   diagnóza   MeSH
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• nemoc štěpu proti hostiteli * MeSH
• prognóza MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

• MeSH
• analýza jednotlivých buněk MeSH
• buňky kostní dřeně metabolismus   MeSH
• dítě MeSH
• HEK293 buňky MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• Kaplanův-Meierův odhad MeSH
• klonální evoluce genetika   MeSH
• klonální hematopoéza genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• myelodysplastické syndromy genetika   patologie   MeSH
• nádorové supresorové proteiny genetika   MeSH
• předškolní dítě MeSH
• transkripční faktor GATA2 genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• zárodečné mutace genetika   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
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Publikační typ
• tisková chyba MeSH

BACKGROUND: Bone marrow (BM) samples obtained from minimal residual disease (MRD)-negative children with B-cell acute lymphoblastic leukemia (B-ALL) were used in our laboratory as negative biological controls for the development of a neuroblastoma (NBL) flow-cytometric (FC) protocol. The accidental, but systematic, identification of rare cell populations (RCP) mimicking NBL cells (CD45- /CD56+ ) in these samples indicated the need for their thorough immunophenotypic identification, in order to elucidate their possible interference in NBL-MRD assessment. PROCEDURE: RCP observed in BM samples from 14 children recovering from BM aplasia due to intensive chemotherapy for B-ALL were investigated with the following markers: CD81, CD200, CD24, GD2, CD73, CD13, CD90, CD146, CD9, CD117, CD10, CD99, and NG2. BM samples from six newly diagnosed patients with NBL and an NBL cell line were simultaneously investigated as positive controls. RESULTS: The frequency of RCP in B-ALL BM samples was < 1/1 × 104 cells (bulky lysis), and their immunophenotypic profile was indicative of CD56+ mesenchymal stromal cells (MSCs) (CD45- , CD90+ , CD146+ , CD73+ ). Also, RCP expressed CD81 and CD200, simulating NBL cells. The most useful discriminative markers for CD56+ MSCs were CD13 and CD73. An appropriate protocol consisting of two tubes with seven color combinations was further proposed: SYTO-16, GD2 (first tube) or CD73 (second tube)-PE, CD24-ECD, CD13-PC5.5, CD45-PC7, CD81-APC, and CD56-APC700. CONCLUSIONS: RCP that were immunophenotypically similar to NBL were identified as CD56+ MSCs. As these cells might pose an obstacle to accurate NBL disease assessment by FC, especially MRD, an enhanced NBL-FC protocol is proposed for prospective evaluation.

• MeSH
• antigeny CD45 metabolismus   MeSH
• antigeny CD56 metabolismus   MeSH
• imunofenotypizace MeSH
• kostní dřeň metabolismus   patologie   MeSH
• lidé MeSH
• mezenchymální kmenové buňky metabolismus   patologie   MeSH
• následné studie MeSH
• neuroblastom diagnóza   etiologie   metabolismus   MeSH
• pre-B-buněčná leukemie komplikace   metabolismus   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• prospektivní studie MeSH
• průtoková cytometrie MeSH
• reziduální nádor etiologie   metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

• MeSH
• akutní bifenotypická leukemie diagnóza   etiologie   terapie   MeSH
• biologické markery MeSH
• dítě MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• management nemoci MeSH
• mladiství MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH