Search

Preleukemic fusion genes (PFGs) occurring after DNA damage in hematopoietic stem progenitor cells (HSPCs) in utero often represent the initial event in the development of childhood leukemia. While the incidence of PFGs characteristic for acute lymphoblastic leukemia (ALL) was relatively well examined by several research groups and estimated to be 1-5% in umbilical cord blood (UCB) of healthy newborns, PFGs that are relevant to acute myeloid leukemia (AML) were poorly investigated. Therefore, this study is focused on the estimation of the incidence of the most frequent AML PFGs in newborns. For the first time, this study considered the inducibility of AML PFGs in different subsets of UCB HSPCs by low-dose γ-rays and also compared endogenous DNA damage, apoptosis, and reactive oxygen species (ROS) level between UCB samples containing or lacking AML PFGs. We found that: (i) the incidence of AML PFGs in UCB was 3.19% for RUNX1-RUNX1T1, 3.19% for PML-RARα, and 1.17% for KMT2A-MLLT3, (ii) 50 cGy of γ-rays did not induce RUNX1-RUNX1T1, PML-RARα, or KMT2A-MLLT3 PFGs in different subsets of sorted and expanded HSPCs, and (iii) the AML PFG + samples accumulated the same level of endogenous DNA damage, as measured by the γH2AX/53BP1 focus formation, and also the same ROS level, and apoptosis as compared to PFG - controls. Our study provides critical insights into the prevalence of AML PFGs in UCB of newborns, without the evidence of a specific HSPC population more susceptible for PFG formation after irradiation to low-dose γ-rays or increased amount of ROS, apoptosis and DNA damage.

Background: The prevalence of autoimmune thyroiditis (AIT), as the most common autoimmune disease (AD) and papillary thyroid cancer (PTC) is steadily rising in children. The aim of this study was to determine the coexistence of other AD and thyroid carcinoma (TC) in AIT., Methods: The cross-sectional study conducted at a tertiary center comprised AIT children (< 19 years). Data on age/sex, thyroid function and ultrasound, autoantibodies, associated AD, familial occurence of AD and the occurence of TC for each child were collected., Results: In total, 231 eligible patients (77% females) were included. The most common onset (66%) was during adolescence. At onset, hypothyroidism was detected in 59.3%; hashitoxicosis in 1.3%. The positivity of both autoantibodies was present in 60.6%, the negativity was in 3,5%. We confirmed a high frequency (44.6%) of AD with AIT predominance in parents and/or grandparents of patients and in siblings (7.4%). 15.2% had at least 1 comorbid AD, of which type 1 diabetes mellitus was the most common (8.5%). Over a period of 7 years TC was diagnosed in 16 patients (mean age 13.5 years) with predominance of PTC in 15 (94%) patients. AIT had concurrently 69% patients. 56% of patients had metastases (89% in AIT subjects). An invasive PTC was present in 44% (86% in AIT subjects)., Conclusions: The prevalence rate of AD in AIT and first-degree relatives is high, and several new associations have been reported. Providers should be aware of comorbidities and TC in AIT as this would help in early diagnoses and timely interventions.

Diamond-Blackfan anemia is a rare inherited bone marrow failure syndrome diagnosed in early infancy that is characterized by a (a) macrocytic anemia with no other significant cytopenia, (b) reticulocytopenia, and (c) normal bone marrow cellularity with a paucity of erythroid precursors. Physical anomalies are often present. Mutations in several ribosomal proteins have been associated with the disease. Here we present a detailed description of 39 patients from 34 families enrolled in the Czech National Diamond-Blackfan Anemia Registry. Erythrocyte adenosine deaminase activity and serum erythropoietin levels were measured and bone marrow analysis and clonogenic assays were carried out. Twenty-two different ribosomal proteins were sequenced. We identified mutations in five different ribosomal proteins in 28/39 patients (71.8%) from 23/34 families (67.6%). Several new mutations are described. The most interesting data relate to genotype-phenotype correlations. All patients with ribosomal protein L5 or ribosomal protein L11 mutations have a thumb defect usually with one or more other anomalies. Most of these patients were born small for gestational age and currently have short stature. We also described five patients with a ribosomal protein S26 mutation. All of the latter are transfusion-dependent and they exhibit skeletal abnormalities rather than thumb or craniofacial deformities. Patients with ribosomal protein S19 seem to bear mildest associated anomalies, usually in a craniofacial region., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia that is usually diagnosed during early infancy. Apart from defects in red blood cell maturation, the disorder is also associated with various physical anomalies in 40% of patients. Mutations in the ribosomal protein (RP) S19 are found in 25% of patients, while mutations in other proteins of the small ribosomal subunit--RPS17 and RPS24--have been found in a fraction of patients. Recently, mutations in RPL5, RPL11, and RPL35a of the large ribosomal subunit have also been reported in several DBA patients. Here, we present the identification of mutations in the RPL5 and RPL11 genes in patients from the Czech DBA Registry. Mutations in RPL5 were identified in eight patients from 6 out of 28 families (21.4%), and mutations in RPL11 in two patients from 2 out of 28 families (7.1%). Interestingly, all 10 patients with either an RPL5 or RPL11 mutation exhibited one or more physical anomalies; specifically, thumb anomalies (flat thenar) were always present, while no such anomaly was observed in seven patients with an RPS19 mutation. Moreover, 9 out of 10 patients with either an RPL5 or RPL11 mutation were born small for gestational age (SGA) compared to 3 out of 7 patients from the RPS19-mutated group. These observations may suggest that mutations, at least in RPL5, seem to generally have more profound impact on fetal development than mutations in RPS19. Since RPL5 and RPL11, together with RPL23, are also involved in the MDM2-mediated p53 pathway regulation, we also screened the RPL23 gene for mutations; however, no mutations were identified., (2009 Wiley-Liss, Inc.)

Background: Thymidine kinase (TK) is involved in nucleic acid synthesis and is therefore considered to be an important proliferation tumor marker. Our main goal was to determine the significance of elevated TK levels as a relapse marker during follow-up with child patients suffering from acute leukemia., Patients and Methods: TK serum levels in 38 children with acute leukemia (34 lymphoblastic, 4 myeloblastic) were determined using radio-receptor analysis (RRA, Immunotech, Prague, USA). All patients included in this study had had TK examined before the start of the treatment and at least twice during the follow-up., Results: Our results showed that TK serum levels at the time of diagnosis were extremely high (78-5826 U/l, median value 403 U/l, normal < 8 U/l), while in remission TK serum levels were much lower (5-80 U/l, median value 31 U/l). During relapse of acute leukemia (5 cases), TK levels increased considerably to measurements between 120-800 U/l (median value 324 U/l). The study showed that the elevation of TK serum levels during follow-up was a helpful marker for the recognition of an early stage of relapse and in some cases occurred as early as one month before the appearance of clinical signs. Sensitivity in this case was 87% and thus TK serum levels seem to be a very good parameter during follow-up because of acceptable sensitivity, low cost (4 $/sample) and the elimination of a requirement for screening of bone marrow samples., Conclusion: While TK serum levels were helpful in predicting relapse during follow-up, it is necessary to note that they did not correlate with prognosis in our group of patients during the time of the initial diagnosis of acute leukemia.

Ribosomal protein S19 (RPS19) is currently the only gene associated with Diamond-Blackfan anemia (DBA), a rare congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. RPS19 is mutated in 25% of DBA patients, but its role in DBA pathogenesis remains elusive. We have identified a novel heterozygous microdeletion in RPS19 in a DBA patient presenting with profound anemia after birth. The deletion of 18 nucleotides (233-250; A in start codon is +1) in exon 4 leads to the elimination of 6 amino acids 78IYGGRQ83, affecting the most conserved stretch of three amino acids (YGG) in RPS19. The mutated allele was not detected in the patient's family members, indicating de novo mutation. Both alleles were expressed at the same level. Using an immunofluorescence technique, the mutated RPS19 protein localized to nucleoli, and its intracellular distribution did not differ from the wild-type RPS19. The deletion of only a few amino acids of this protein with a preserved reading frame is rare, and this type of a mutation could be very helpful in further experiments to define the role of the RPS19 protein in DBA pathogenesis.