Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2R715T kinase. Similar to PV, the JAK2R715T native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2V617F PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2R715T gain-of-function mutation with many but not all comparable molecular features to JAK2V617F PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.

• MeSH
• aktivační mutace MeSH
• dospělí MeSH
• interferon alfa terapeutické užití   MeSH
• Janus kinasa 2 * genetika   MeSH
• lidé MeSH
• polycytemie * genetika   farmakoterapie   MeSH
• polycythaemia vera genetika   farmakoterapie   MeSH
• rodokmen MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Diabetes mellitus matiek sa podieľa na vzniku mnohých patologických stavov u ich potomkov. Novorodenci diabetických matiek sú často makrozómni a v zvýšenej miere sa u nich vyskytuje pôrodný traumatizmus, hypoglykémia, hypokalcémia, polycytémia, hyperbilirubinémia, respiračná tieseň novorodenca, kardiomyopatia, vrodené vývojové chyby a poruchy gastrointestinálneho traktu. Z dlhodobého hľadiska sú deti diabetických matiek ohrozené vznikom neurologických a metabolických porúch, na ktorých vzniku sa podieľajú epigenetické zmeny. Uvedené riziká a komplikácie u detí významne redukuje dôsledná kontrola diabetu matiek v prekoncepčnom období a počas gravidity.

Diabetes mellitus in mothers is involved in the development of many pathological conditions in their offspring. Infants of diabetic mothers are often macrosomic and have an increased incidence of birth trauma, hypoglycemia, hypocalcemia, polycythemia, hyperbilirubinemia, neonatal respiratory distress syndrome (IRDS), cardiomyopathy, congenital malformations, and gastrointestinal tract disorders. In the long term, infants of diabetic mothers are at risk of developing neurological and metabolic disorders, which are caused by epigenetic changes. The mentioned risks and complications in children are significantly reduced by rigorous control of maternal diabetes in the preconception period and during pregnancy.

• MeSH
• diabetes mellitus terapie   MeSH
• gastrointestinální trakt patologie   MeSH
• gestační diabetes diagnóza   MeSH
• hyperbilirubinemie diagnóza   etiologie   terapie   MeSH
• hypoglykemie diagnóza   etiologie   prevence a kontrola   MeSH
• hypokalcemie diagnóza   etiologie   MeSH
• kardiomyopatie diagnóza   etiologie   terapie   MeSH
• lidé MeSH
• makrosomie plodu etiologie   komplikace   MeSH
• polycytemie diagnóza   etiologie   terapie   MeSH
• porodní poranění novorozence MeSH
• syndrom respirační tísně novorozenců diagnóza   etiologie   terapie   MeSH
• těhotenství při diabetu * MeSH
• těhotenství MeSH
• vrozené poruchy metabolismu diagnóza   etiologie   MeSH
• vrozené vady diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH

Obstructive sleep apnea (OSA) causes intermittent hypoxia during sleep. Hypoxia predictably initiates an increase in the blood hemoglobin concentration (Hb); yet in our analysis of 527 patients with OSA, >98% did not have an elevated Hb. To understand why patients with OSA do not develop secondary erythrocytosis due to intermittent hypoxia, we first hypothesized that erythrocytosis occurs in these patients, but is masked by a concomitant increase in plasma volume. However, we excluded that explanation by finding that the red cell mass was normal (measured by radionuclide labeling of erythrocytes and carbon monoxide inhalation). We next studied 45 patients with OSA before and after applying continuous positive airway pressure (CPAP). We found accelerated erythropoiesis in these patients (increased erythropoietin and reticulocytosis), but it was offset by neocytolysis (lysis of erythrocytes newly generated in hypoxia upon return to normoxia). Parameters of neocytolysis included increased reactive oxygen species from expanded reticulocytes' mitochondria. The antioxidant catalase was also downregulated in these cells from hypoxia-stimulated microRNA-21. In addition, inflammation-induced hepcidin limited iron availability for erythropoiesis. After CPAP, some of these intermediaries diminished but Hb did not change. We conclude that in OSA, the absence of significant increase in red cell mass is integral to the pathogenesis, and results from hemolysis via neocytolysis combined with inflammation-mediated suppression of erythropoiesis.

• MeSH
• hepcidiny MeSH
• hypoxie MeSH
• lidé MeSH
• obstrukční spánková apnoe * komplikace   MeSH
• polycytemie * etiologie   MeSH
• reaktivní formy kyslíku MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

• Klíčová slova
• ropeginterferon alfa‐2 b,
• MeSH
• dospělí MeSH
• indukce remise MeSH
• interferon alfa-2 * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• polycytemie * diagnóza   farmakoterapie   komplikace   MeSH
• separace krevních složek metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.

• MeSH
• hepcidiny genetika   MeSH
• iontové kanály genetika   MeSH
• kyslík metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• polycytemie * genetika   MeSH
• receptory erythropoetinu genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• anemie diagnóza   etiologie   terapie   MeSH
• hemoragické poruchy diagnóza   etiologie   terapie   MeSH
• hypochromní anemie diagnóza   etiologie   terapie   MeSH
• komorbidita MeSH
• krevní nemoci * diagnóza   etiologie   terapie   MeSH
• leukemie diagnóza   terapie   MeSH
• lidé MeSH
• lymfoidní leukemie diagnóza   farmakoterapie   patologie   MeSH
• lymfom diagnóza   patologie   terapie   MeSH
• makrocytární anemie diagnóza   etiologie   terapie   MeSH
• polycytemie diagnóza   etiologie   terapie   MeSH
• trombofilie diagnóza   etiologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• lidé MeSH
• nemoci novorozenců MeSH
• novorozenec MeSH
• polycytemie * diagnóza   patologie   terapie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• krevní nemoci * patofyziologie   terapie   MeSH
• lidé MeSH
• neonatální anemie MeSH
• novorozenec MeSH
• novorozenecká žloutenka MeSH
• polycytemie MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

Iron availability for erythropoiesis is controlled by the iron-regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain-of-function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3-6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age-related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive-mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose-dependent alterations of downstream EPOR stimulation.

• MeSH
• aktivační mutace MeSH
• dospělí MeSH
• erythropoetin * genetika   farmakologie   MeSH
• erytropoéza genetika   MeSH
• hepcidiny genetika   metabolismus   MeSH
• hormony MeSH
• lidé MeSH
• myši MeSH
• polycytemie * genetika   MeSH
• receptory erythropoetinu genetika   metabolismus   MeSH
• senioři MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• myši MeSH
• senioři MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: Databáze MIND (MyeloprolIferative Neoplasia Database) vznikla v květnu 2013 pod záštitou České leukemické skupiny pro život a sbírá data od pacientů s Ph negativními myeloproliferativními neopláziemi (Ph-MPN) sledovaných v participujících českých hematologických centrech. Cílem této práce je analýza zadaných dat pacientů a jejich srovnání s publikovanými mezinárodními výsledky. Materiál a metodika: Retrospektivní neintervenční multicentrická analýza byla provedena u celkem 641 validních pacientů s Ph-MPN zadaných do databáze MIND v období 2013–2020. Hodnocena byla data týkající se epidemiologie, diagnostiky, léčby a prognózy. Výsledky: Medián sledování pacientů v souboru byl 35 měsíců. Nejvíce byla zastoupena pravá polycytémie, PV (34 %), primární myelofibróza, PMF (31 %) a esenciální trombocytémie, ET (22 %). Z doprovodných příznaků se při stanovení diagnózy nejčastěji vyskytovaly únava (52 %), noční pocení (32 %), snížená aktivita (30 %) a svědění kůže (27 %). Splenomegalie byla přítomna u více než poloviny pacientů s PMF (54 %). Mutace JAK2 V617F byla zachycena u 90 % PV, 65 % PMF a 62 % ET; mutace CALR u 22 % ET a 16 % PMF. Cytogenetické abnormality byly pozorovány signifikantně frekventněji u PMF a PV oproti ET (17 a 15 vs. 3 % vyšetřených pacientů; p ≤ 0,005). Nejčastější komplikace v době diagnózy představovaly trombotické (22 %) a krvácivé příhody (10 %) bez signifikantního rozdílu četnosti mezi typy Ph-MPN (p > 0,017). U PV byla v 1. i 2. linii léčby nejčastěji podávána hydroxyurea (72 a 65 %), u ET v obou liniích anagrelid (52 a 82 %), u PMF v 1. linii hydroxyurea (70 %) a ve 2. linii ruxolitinib (30 %). Leukemická transformace byla zachycena u 3 % Ph-MPN, a to pouze u MF (10 %). Zemřelo celkem 17 % případů, nejvíce PMF (53 %). Medián celkového přežití nebyl dosažen u ET, na rozdíl od nejkratšího mediánu u sekundární MF (2,5 roku). U PMF měly nejnižší celkové přežití skupiny pacientů s vyšším věkem, vyšším IPSS a s mutací JAK2 V617F. Závěr: Potvrdili jsme četný výskyt symptomů zhoršujících kvalitu života pacientů s Ph-MPN. Cytogenetické abnormality byly sledovány výrazně častěji u pacientů s PMF a PV oproti ET. Trombotické a krvácivé události v době diagnózy provázely stejně frekventně PV, ET i PMF. Nejdéle přežívali pacienti s PV, zato u pacientů s MF byly pozorovány nejčastější leukemické transformace a nejnižší křivka přežívání. Vyšší věk, vyšší IPSS a přítomnost mutace JAK2 V617F se projevily jako faktory asociované s horším přežíváním pacientů s PMF.

Background: Our MIND database was initiated on May 1, 2013, with the primary objective of collecting data from patients with Ph negative myeloproliferative neoplasms (Ph-MPN) in Czech haematological centres. The principal aim was to analyse and compare our patient data with published data. Patients and Methods: A total of 641 valid Ph-MPN patients registered in MIND were analysed from 2013 to 2020. Epidemiology, diagnostics, therapy and prognosis were evaluated. Results: With a 35-month median follow-up, the most common diagnosis was polycythaemia vera- PV (34%) followed by primary myelofibrosis, PMF (31%) and essential thrombocythemia, ET (22%). At the time of diagnosis, patients suffered mostly from fatigue (52%), night sweats (32%), weakness (30%) and itching (27%). Splenomegaly occurred in more than half of PMF patients (54%). The JAK2 V617F mutation was present in 90% of PV, 65% of PMF and 62% of ET, respectively. The CALR mutation was found in 22% of ET and 16% of PMF, respectively. Cytogenetic abnormalities were significantly more frequently documented in both PMF and PV compared to ET (17 and 15 vs. 3% of examined patients, respectively; P ≤ 0.005). Thrombosis (22%) and bleeding (10%) were the most common complications at diagnosis with no significant difference in frequency among PV, ET, and PMF, respectively (P > 0.017). In PV, hydroxyurea was the most frequently used drug as both 1st and 2nd line treatment (72 and 65%, respectively). Anagrelide was used in both lines in ET (52 and 82%, respectively) and hydroxyurea was used as 1st line treatment with ruxolitinib as 2nd line treatment in PMF (70 and 30%, respectively). Leukemic transformation was detected in 3% of Ph-MPN and only in MF (10%). 17% of our patients died, most from PMF (53%). Median overall survival was not attained in ET, contrasting with the lowest median in secondary MF (2.5 years). In PMF, median overall survival was decreased by dotage, higher IPSS, and JAK2 V617F mutation presence. Conclusion: We have recognized a recurring definitive frequency of symptoms that exacerbate patient quality of life. A higher incidence of additional cytogenetic abnormalities was recorded more frequently with both PMF and PV compared to ET. During diagnosis, thrombotic and bleeding events were present with no significant difference in frequency among PV, ET, and PMF. Overall survival median was the longest in PV, compared to MF with the most frequent leukemic transformations and the lowest survival. In PMF, higher age, higher IPSS and JAK2 V617F presence were shown as factors shortening survival.

• Klíčová slova
• Ph negativní myeloproliferativní onemocnění,
• MeSH
• esenciální trombocytemie diagnóza   epidemiologie   terapie   MeSH
• lidé MeSH
• myeloproliferativní poruchy * diagnóza   epidemiologie   terapie   MeSH
• polycytemie diagnóza   epidemiologie   terapie   MeSH
• primární myelofibróza diagnóza   epidemiologie   terapie   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH