Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.
- MeSH
- chromozomální delece MeSH
- dítě MeSH
- fetální hemoglobin metabolismus MeSH
- juvenilní myelomonocytární leukemie genetika MeSH
- lidé MeSH
- lidské chromozomy, pár 7 genetika MeSH
- multivariační analýza MeSH
- nádorové biomarkery metabolismus MeSH
- plod metabolismus MeSH
- předškolní dítě MeSH
- přežití po terapii bez příznaků nemoci MeSH
- prognóza MeSH
- proteiny vázající RNA genetika metabolismus MeSH
- regulace genové exprese u leukemie MeSH
- transplantace hematopoetických kmenových buněk MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult β-hemoglobin: β-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment.
- MeSH
- dítě MeSH
- dospělí MeSH
- fetální hemoglobin biosyntéza genetika MeSH
- introny MeSH
- jaderné proteiny genetika metabolismus MeSH
- jednonukleotidový polymorfismus MeSH
- kojenec MeSH
- lidé MeSH
- pervazivní vývojové poruchy u dětí genetika metabolismus patologie MeSH
- předškolní dítě MeSH
- regulace genové exprese MeSH
- schizofrenie genetika metabolismus patologie MeSH
- sekvence nukleotidů MeSH
- sekvenční delece MeSH
- transportní proteiny genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
Cíl: Stanovení fetálního hemoglobinu (HbF) je důležité pro diagnostiku hemoglobinopatií a jiných onemocnění. Cílem naší práce bylo zhodnotit možnost presumptivního stanovení HbF v modu pro stanovení glykovaného hemoglobinu (HbA1c) na automatickém HPLC analyzátoru Tosoh HLC-723 G7. Materiál a metody: K analýze HbF v modu pro stanovení HbA1c bylo použito 63 vzorků nesrážlivé krve. Vzorky byly rozděleny do 3 skupin: 1. skupina (n = 24), HbF v intervalu 1–2 % z celkového hemoglobinu (Hb); 2. skupina (n = 21), HbF v intervalu 2–5 % z celkového Hb; 3. skupina (n = 18), HbF > 5 % z celkového Hb. U těchto vzorků byl zároveň kvantifikován HbF v thalasemickém modu stejného přístroje. Výsledky: Hodnoty HbF mezi 1–2 % spolu nekorelovaly (r = 0,241). Naopak byla nalezena korelace hodnot mezi 2–5 % (r = 0,825; p < 0,001), stejně tak jako hodnot HbF > 5 % (r = 0,889; p < 0,001). Klinický význam mají především hodnoty patologické, tedy hodnoty HbF větší než 2 % z celkového Hb. Takové hodnoty stanovené v modu pro analýzu glykovaného hemoglobinu je možno pokládat za správné. Naopak hodnoty HbF pod 2 % z celkového Hb stanovené v modu pro glykovaný hemoglobin nejsou analyticky správné. Závěr: Závěrem je možné konstatovat, že analytický mod pro stanovení glykovaného hemoglobinu na analyzátoru Tosoh HLC-723 G7 je možné použít také pro presumptivní kombinované HPLC stanovení fetálního hemoglobinu.
Objective: Measurement of foetal hemoglobin (HbF) has an important clinical value in the diagnosis as well as in characterization of some Hb structural variants and other hemoglobinopathies. We evaluated presumptive HbF quantification in analytical mode for glycated hemogobin (HbA1c) on Tosoh HLC-723 G7 analyser. Material and Methods: We analysed 63 blood samples and quantified HbF by mode for glycated hemoglobin. The samples were sorted to 3 groups according HbF values: group 1 (n = 24) included HbF values 1–2 % of total hemoglobin (Hb), group 2 (n = 21) included HbF values 2–5 % of total Hb, and group 3 (n = 18) included HbF > 5 % of total Hb. We simultaneously measured HbF in all samples in mode for β-thalassemia determination on the same analyser. Results: The HbF values between 1–2 % obtained by glycated mode did not correlated with results by β-thalassemia mode (r = 0.241). The both HbF values between 2–5 % and HbF values > 5 % of total Hb correlated acceptable with results by β-thalassemia mode (r = 0.825 and 0.889 respectively; p < 0.001). Only pathological HbF values higher than 2 % of total Hb have the clinical significance. These values measured by mode for HbA1c determination is possible to take as correct. On the contrary, all HbF values lower then 2 % of total Hb, measured by mode for HbA1c determination, are not reliable. Conclusion: We conclude that analytical mode for HbA1c determination is also suitable to use for presumptive combined HbF quantification on Tosoh HLC-723 G7 analyser.
- MeSH
- etnicita MeSH
- Fanconiho anemie etiologie MeSH
- fetální hemoglobin MeSH
- lidé MeSH
- superoxiddismutasa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
We have identified through sequencing of amplified DNA a GCC-->GAC mutation in codon 115 of the beta-globin gene in a mother and daughter of a small Czech family. This base change was confirmed by hybridization with a 32P-labeled specific oligonucleotide probe and by gene mapping because it creates a new Ava II site. The mutation results in an Ala-->Asp replacement at beta 115(G17); this beta chain is severely unstable and could not be identified either as chain or as hemoglobin variant by isoelectrofocusing and various high performance liquid chromatography methods. Stability tests were mildly positive in freshly prepared lysates, but an unstable hemoglobin could not be detected in older lysates with these methods. Its presence results in a dominant type of beta-thalassemia in the two heterozygotes, with moderate anemia, reticulocytosis, nucleated red cells, target cells, and other red cell changes, Heinz body formation, and splenomegaly; the oldest of the two patients was splenectomized. Both subjects had a marked increase in fetal hemoglobin synthesis.
- MeSH
- beta-talasemie genetika MeSH
- bodová mutace MeSH
- dominantní geny MeSH
- dospělí MeSH
- fetální hemoglobin biosyntéza MeSH
- globiny genetika MeSH
- hemoglobiny abnormální genetika izolace a purifikace MeSH
- heterozygot MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutační analýza DNA MeSH
- předškolní dítě MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Geografické názvy
- Česká republika MeSH
We have identified through sequencing of amplified DNA a GCC-->GAC mutation in codon 115 of the beta-globin gene in a mother and daughter of a small Czech family. This base change was confirmed by hybridization with a 32P-labeled specific oligonucleotide probe and by gene mapping because it creates a new Ava II site. The mutation results in an Ala-->Asp replacement at beta 115(G17); this beta chain is severely unstable and could not be identified either as chain or as hemoglobin variant by isoelectrofocusing and various high performance liquid chromatography methods. Stability tests were mildly positive in freshly prepared lysates, but an unstable hemoglobin could not be detected in older lysates with these methods. Its presence results in a dominant type of beta-thalassemia in the two heterozygotes, with moderate anemia, reticulocytosis, nucleated red cells, target cells, and other red cell changes, Heinz body formation, and splenomegaly; the oldest of the two patients was splenectomized. Both subjects had a marked increase in fetal hemoglobin synthesis.
- MeSH
- beta-talasemie * genetika MeSH
- bodová mutace MeSH
- dominantní geny MeSH
- dospělí MeSH
- fetální hemoglobin biosyntéza MeSH
- globiny * genetika MeSH
- hemoglobiny abnormální * genetika izolace a purifikace MeSH
- heterozygot MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutační analýza DNA MeSH
- předškolní dítě MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- dějiny starověku MeSH
- fetální hemoglobin MeSH
- hemoglobin A2 MeSH
- kostní dřeň patologie MeSH
- lidé MeSH
- talasemie krev dějiny patologie MeSH
- Check Tag
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- dějiny starověku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- Geografické názvy
- Československo MeSH
- Spojené státy americké MeSH
