Inflammatory and oncogenic signaling converge in disease evolution of BCR-ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34+ progenitor-enriched cultures from JAK2V617F+ PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients' bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFNγ- and NF-κB-associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes' expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1-inhibited parental JAK2V617F+ cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F+ PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

• MeSH
• cytokiny genetika   metabolismus   MeSH
• fosfatasa 1 s dvojí specificitou genetika   MeSH
• hematopoetické kmenové buňky patologie   MeSH
• indukované pluripotentní kmenové buňky patologie   MeSH
• Janus kinasa 2 genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• oxidační stres * MeSH
• polycythaemia vera genetika   MeSH
• poškození DNA * MeSH
• proliferace buněk * MeSH
• reprodukovatelnost výsledků MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• DUSP1 protein, human MeSH Prohlížeč
• fosfatasa 1 s dvojí specificitou MeSH
• JAK2 protein, human MeSH Prohlížeč
• Janus kinasa 2 MeSH
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

• MeSH
• adaptorové proteiny signální transdukční antagonisté a inhibitory   MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• chronická myeloidní leukemie farmakoterapie   metabolismus   MeSH
• fosforylace účinky léků   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• jaderné proteiny antagonisté a inhibitory   MeSH
• lidé MeSH
• průtoková cytometrie MeSH
• skupina kinas odvozených od src-genu antagonisté a inhibitory   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antitumorózní látky MeSH
• CRKL protein MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• jaderné proteiny MeSH
• skupina kinas odvozených od src-genu MeSH

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by an abnormal fusion gene BCR-ABL. BCR-ABL encodes a constitutively active Bcr-Abl tyrosine kinase, which is required and sufficient for cellular transformation. Bcr-Abl is, therefore, an ideal target for pharmacotherapy. Imatinib Mesylate (Glivec) is a specific inhibitor of Bcr-Abl kinase. Imatinib shows high efficiency and low toxicity in treatment of CML patients. The main problem of imatinib treatment is the development of resistance. The mechanisms of resistance can be divided into two groups. The first group is characterized by reactivation of Bcr-Abl kinase in spite of continual imatinib presence. This can be caused by BCR-ABL amplification, overexpression or mutation in Abl kinase domain. Imatinib might not even reach the target Bcr-Abl protein (possible causes: drug efflux or imatinib binding to alpha1-acid glycoprotein). In the second group of resistance mechanisms, the Bcr-Abl kinase is inhibited but the resistance is maintained by other signal transducers (e.g. Src kinases). Standard cytogenetics as well as assay evaluating the phosphorylation status of Bcr-Abl substrate and/or sequencing of Abl kinase transcript can be used to test the mechanism of resistance. Treatment of patients can be re-evaluated on the basis of the status of IM resistance.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• bcr-abl fúzové proteiny MeSH
• benzamidy MeSH
• chemorezistence * MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• geny abl fyziologie   MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• piperaziny terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• signální transdukce MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• bcr-abl fúzové proteiny MeSH
• benzamidy MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• piperaziny MeSH
• pyrimidiny MeSH
• tyrosinkinasy MeSH

Cytogenetic and molecular cytogenetic analysis of 79 childhood acute lymphoblastic leukemias (ALL) revealed chromosomal abnormalities in 76 (96%). Complex karyotypes (a finding of three and more chromosomal aberrations in a karyotype) were identified in 21 (26.6%) out of 79 patients. In 11 patients, complex karyotypes have included common recurrent chromosomal abnormalities, such as translocation t(12;21) in seven cases, t(9;22) in two cases, one case with t(2;1;19) and another one with translocation involving 11q23. In 10 patients, miscellaneous abnormalities were detected. Five patients displayed hyperdiploidy (47 approximately 57 chromosomes), three patients complex karyotypes with deletions of 9p, one patient with two new complex translocations t(2;4;12;13) and t(7;11;20), and the last patient with dic(12;21). The evaluation of the frequency of the chromosomal breaks (>5 per chromosome) showed that chromosomes 2, 4, 5, 7, 9, 12, 13, and 21 were most frequently affected. Survival analysis revealed statistically significant unfavorable event-free survival (EFS) (P=0.013) and decreased overall survival in the group with complex karyotypes (n=21) compared with the other cases (n=58). The evaluation of overexpression profile revealed increased occurrence of double CD13/CD33 positivity in patients with common recurrent chromosomal abnormalities (in 70% of cases); no such cases were registered in the other group (P<0.01).

• MeSH
• akutní lymfatická leukemie genetika   MeSH
• CD antigeny genetika   MeSH
• chromozomální aberace * MeSH
• dítě MeSH
• karyotypizace MeSH
• lidé MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CD antigeny MeSH

The authors describe a newly identified beta0-thalassaemic mutation found in two subjects from two generations of a Slovak family. The beta0-thalassaemic allele developed by insertion of one nucleotide (+G, CD 7/8) into the first exon of the beta-globin gene. The mutation causes a shift of the open globin reading frame which leads to the development of a terminal codon in codon 22. The thalassaemic allele is associated with the mediterranean haplotype IX. The mutation has in both heterozygotes the phenotype of beta0-thalassaemia minor with a slightly elevated level of HbF.

• MeSH
• alely MeSH
• beta-talasemie genetika   MeSH
• exony genetika   MeSH
• fenotyp MeSH
• globiny genetika   MeSH
• haplotypy MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• posunová mutace * MeSH
• rodokmen MeSH
• sekvenční analýza DNA MeSH
• terminační kodon genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• globiny MeSH
• terminační kodon MeSH

The paper demonstrates the importance of sequence analysis of DNA for the identification of Hb-Sydney [alpha2-beta2 67 (E11) Val-Ala]. The latter was considered erroneously, based on results of biochemical analyses to be Hb-M-Milwaukee [alpha2 beta2 67 (E 11) Val-Glu]. With the unstable Hb-Sydney correspond also phenotypical manifestations of disease (haemolytic anaemia with Heinz bodies in red blood cells). Sequence analysis of DNA of patients with Hb-Olomouc [alpha 2 beta 2 (F 2) Ala-Asp] revealed that mutation of Ala-Asp in position 86 (F 2) of the beta globin chain is coded by mutation C-->A (GCC-GAC).

• MeSH
• chybná diagnóza MeSH
• hemoglobinopatie diagnóza   genetika   MeSH
• hemoglobiny abnormální genetika   MeSH
• lidé MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• hemoglobin Olomouc MeSH Prohlížeč
• hemoglobiny abnormální MeSH

The authors describe the identification and the clinical manifestations of a new structural variant of haemoglobin found in three subjects from two generations of a Moravian family. It is manifested by mild haemolytic anaemia with Heinz bodies in the proband and a slightly elevated value of methaemoglobin. The sequential analysis of the beta-globin gene provided evidence that the cause is mutation CAT-AAT in codon 63 which leads to the exchange of distal histidine /E7/ for asparagine. The ratio of beta X:beta A is 38:62. The mother with the same mutation is asymptomatic. The relative amount of beta X:beta A mRNA transcripts in mother and daughter are equal. This indicates that the clinical differences are not due to a different gene expression. The mother is a heavy smoker with an elevated CO-Hb level that probably protect the mutant against oxidative denaturation and increases thus the stability of Hb-Haná. The authors discuss also the finding of two abnormal stripes assessed by three electrophoretic methods.

• MeSH
• bodová mutace MeSH
• dítě MeSH
• exprese genu * MeSH
• globiny genetika   MeSH
• hemoglobiny abnormální genetika   MeSH
• kojenec MeSH
• kongenitální hemolytická anemie genetika   MeSH
• kouření genetika   MeSH
• lidé MeSH
• methemoglobinemie genetika   MeSH
• rodokmen MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• globiny MeSH
• hemoglobiny abnormální MeSH

A retrospective analysis of the treatment with Interferon alpha in 18 patients with Ph positive chronic myeloid leukaemia is presented and compared with the results of peroral chemotherapy with Hydroxyurea or Busulphan in 20 patients. Patients treated with Interferon were significantly younger than the control group (median age 40.5 versus 55.5) (p = 0.01) and were followed-up for shorter period of time (median 10.5 months versus 36.5 months) ( p = 0.002), but did not differ in other parameters. Despite the shorter period of observation and treatment, significantly more complete haematological remissions were achieved with Interferon (86%) than with peroral chemotherapy (25%) (p = 0.03). 6 major and 2 minor (44%) cytogenetic responses were observed after Interferon, despite the fact that 8 patients had been treated for less than one year. Interferon was not the optimal therapy in the patients with additional or complex cytogenetic abnormalities at the time of diagnosis, which were the most significant negative prognostic factor. In general, our short-term results confirm the importance and effectiveness of Interferon in the patient with CML providing the therapy was started early, with an effective dose and with simultaneous cytogenetic monitoring. Longer observation of the patients is needed to confirm the impact of Interferon on the survival of patients.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• busulfan terapeutické užití   MeSH
• chronická myeloidní leukemie terapie   MeSH
• dospělí MeSH
• hydroxymočovina terapeutické užití   MeSH
• interferon alfa terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři 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
• anglický abstrakt MeSH
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• klinické zkoušky MeSH
• Názvy látek
• antitumorózní látky MeSH
• busulfan MeSH
• hydroxymočovina MeSH
• interferon alfa MeSH

The unstable haemoglobin variant Ana (alpha 2 beta 2 88 (F4) Leu-Pro) was identified to cause haemolysis in a 10-year-old Slovak girl. She was followed for haemolytic anaemia symptoms since two years of age. Clinical signs are hepatosplenomegaly and moderate haemolytic anaemia not requiring blood transfusions. It is the first case of an unstable haemoglobinopathy found in Slovak Republic as far as we know. Hypothesis of 'de novo' origin of the mutation in the propositus is supported by the parents' and brother's laboratory findings.

• MeSH
• bodová mutace MeSH
• dítě MeSH
• hemoglobiny abnormální genetika   MeSH
• kongenitální hemolytická anemie krev   genetika   MeSH
• lidé MeSH
• sekvence nukleotidů MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• hemoglobiny abnormální MeSH

The authors present a review of clinical and laboratory findings of seven in the Czech Republic hitherto diagnosed structural haemoglobin variants. Unstable variants are found most frequently: Hb-Köln, Hb-St. Louis, Hb-Nottingham, Hb-E and Hb-Hradec Králové. The variant Hb-Hradec Králové (Hb-HK) or alpha 2 beta 2 115 (G17) Ala-Asp was newly detected. The great instability of Hb-HK chains makes classical diagnosis of Hb-pathy impossible. It was possible to identify it only at a molecular genetic level. A manifestation of Hb-HK instability is also the thalassaemic feature of the disease and the formation of Heinz bodies from free chains. The only representative of haemoglobins with a high oxygen affinity identified in this country was newly detected. It was given the name Hb-Olomouc or alpha 2 beta 2 86 (F2) Ala-Asp. This haemoglobin variant leads to erythrocytosis in father and son and the same clinical manifestations were recently described also in Japan. The last structural variant of haemoglobin found in this country is Hb-M Milwaukee or alpha 2 beta 2 67 (E11) Val-Glu which in our patients is manifested rather by haemolysis with formation of Heinz bodies than classical cyanosis. The cause of instability of Hb-M in our patients is not known. Hb-S was not diagnosed so far in the Czech Republic.

• MeSH
• dospělí MeSH
• hemoglobinopatie epidemiologie   genetika   MeSH
• hemoglobiny abnormální analýza   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• rodokmen MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• hemoglobiny abnormální MeSH