• Klíčová slova
• PHF6, cytogenetics, mutation analysis, myeloid leukaemia, paediatric oncology,
• MeSH
• akutní myeloidní leukemie genetika   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• represorové proteiny MeSH
• transportní proteiny genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• PHF6 protein, human MeSH Prohlížeč
• represorové proteiny MeSH
• transportní proteiny MeSH

Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML-associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient-derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late-acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia-transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non-specific order of acquisition.

• Klíčová slova
• acute myeloid leukaemia, clonality, mutations, patient-derived xenograft, relapse,
• MeSH
• akutní myeloidní leukemie farmakoterapie   genetika   terapie   MeSH
• buněčné klony MeSH
• dospělí MeSH
• geny nádorové * MeSH
• heterografty MeSH
• klonální evoluce MeSH
• kombinovaná terapie MeSH
• leukocyty MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace * MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové kmenové buňky MeSH
• nádorové proteiny genetika   MeSH
• nukleofosmin MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové proteiny MeSH
• NPM1 protein, human MeSH Prohlížeč
• Npm1 protein, mouse MeSH Prohlížeč
• nukleofosmin MeSH

INTRODUCTION: To date, no chemoresistance predictors are included in acute myeloid leukaemia (AML) prognostic scoring systems to distinguish responding and refractory AML patients prior to chemotherapy. ABC transporters have been described as altering AML chemosensitivity; however, a relevant study investigating their role at various molecular levels was lacking. METHODS: Gene expression, genetic variants, methylation and activity of ABCA2, ABCA5, ABCB1, ABCB6, ABCC1, ABCC3 and ABCG2 were analysed in AML blasts and healthy myeloblasts. Differences between responding and refractory AML in a cohort of 113 patients treated with 3 + 7 induction therapy were explored. RESULTS: ABCC3 variant rs2301837 (p = 0.049), ABCG2 variant rs11736552 (p = 0.044), higher ABCA2 (p = 0.021), ABCC1 (p = 0.017), and ABCG2 expression (p = 0.023) and a higher number of concurrently overexpressed transporters (p = 0.002) were predictive of treatment failure by multivariate analysis. Expression of ABCA5 (p = 0.003), ABCB6 (p = 0.001) and ABCC3 (p < 0.0001) increased significantly after chemotherapy. Higher ABCG2 promoter methylation correlated with lower ABCG2 expression (p = 0.0001). ABCC1 was identified as the most active transporter in AML blasts by functional analysis. CONCLUSIONS: ABC transporters, especially ABCC1 seem to contribute substantially to AML chemoresistance. A detailed understanding of chemoresistance mechanisms and the clinical implications of chemosensitivity predictors may lead to alternative therapeutic approaches for AML patients with unveiled chemoresistance signatures.

• Klíčová slova
• ABC transporter, Acute myeloid leukemia, Anthracycline, Chemoresistance,
• MeSH
• ABC transportéry * metabolismus   MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   MeSH
• chemorezistence genetika   MeSH
• lidé MeSH
• terapie neúspěšná MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry * MeSH

Acute myeloid leukaemia (AML) is the leading form of fatal acute leukaemia in adults. AML is a heterogeneous disease with respect to responsible mutations and chromosomal abnormalities as well as to their clinicopathological image. In recent years, great progress has been made in techniques allowing detection of genetic changes in both de novo AML and in secondary AML induced by other haematological disorders or therapy, and in detection of residual disease after therapy. Accumulated knowledge allowed better understanding of the molecules and mechanisms involved not only in the formation and expansion of a primary leukaemia-founding clone, but also of a temporal order of changes leading to the fully malignant phenotype. The recent knowledge of bone marrow (BM) compartments and interrelations among various BM resident and recruited cell types helps in understanding the AML development. The progress in the techniques and knowledge will result in the development and use of molecularly targeted therapies tailored to individual patient needs.

• MeSH
• akutní myeloidní leukemie genetika   metabolismus   MeSH
• chromozomální aberace MeSH
• fenotyp MeSH
• kostní dřeň metabolismus   MeSH
• lidé MeSH
• mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Oncogenic mutations in gene encoding FLT3 kinase are often detected in acute myeloid leukaemia (AML) patients, and several potent kinase inhibitors have been developed. However, the FLT3 inhibitor treatment often leads to the resistance development and subsequent relapse. Targeted degradation of oncogenic protein kinases has emerged as a feasible pharmacological strategy, providing more robust effect over traditional competitive inhibitors. Based on previously developed competitive inhibitor of FLT3 and CDK9, we have designed and prepared a novel pomalidomide-based PROTAC. A series of biochemical and cellular experiments showed selectivity towards FLT3-ITD bearing AML cells and confirmed proteasome-dependent mechanism of action. Dual FLT3-ITD and CDK9 protein degradation resulted in the block of FLT3-ITD downstream signalling pathways, apoptosis activation and cell cycle arrest of FLT3-ITD AML cells. Moreover, transcriptional repression caused by CDK9 degradation significantly reduced expression of crucial genes involved in AML pathogenesis. The obtained results indicate the beneficial impact of simultaneous FLT3-ITD/CDK9 degradation for AML therapy.

• Klíčová slova
• Acute myeloid leukaemia, CDK9, FLT3, Proteolysis targeting chimera (PROTAC),
• MeSH
• akutní myeloidní leukemie * patologie   MeSH
• apoptóza MeSH
• cyklin-dependentní kinasa 9 metabolismus   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• proteolýza MeSH
• tyrosinkinasa 3 podobná fms genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CDK9 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 9 MeSH
• FLT3 protein, human MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• tyrosinkinasa 3 podobná fms MeSH

In this multi-centre study, we analysed the prognostic impact of mutations in 19 genes associated with myeloid malignancies in 258 newly diagnosed acute myeloid leukaemia patients (aged 19-70 years) undergoing intensive therapy. We identified five patient groups with different prognostic risks and different benefits from allogeneic hematopoietic stem cell transplantation (alloHSCT) within the intermediate cytogenetic risk group patients (n = 184). The most adverse prognosis was observed in patients with DNMT3A and FLT3-ITD co-mutation, whose survival could be significantly improved with alloHSCT. In contrast, the most favourable prognosis without any further benefit from alloHSCT was identified in patients with mutations in NPM1 or CEBPA, after exclusion of the unfavourable prognostic groups defined by mutations in DNMT3A, RUNX1 or genes from chromatin/spliceosome group. An additional analysis of 113 diagnosis-remission paired samples revealed that persistence of non-DNMT3A mutations (above 2% VAF) represented a further negative prognostic factor. The proposed model offers a possible molecular stratification and treatment guidance for intermediate cytogenetic risk group patients.

• Klíčová slova
• acute myeloid leukaemia, next generation sequencing, persistent mutations, prognostic markers, survival,
• MeSH
• akutní myeloidní leukemie * diagnóza   genetika   terapie   MeSH
• alografty MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• nádorové proteiny genetika   MeSH
• nukleofosmin MeSH
• prognóza MeSH
• progrese nemoci MeSH
• rizikové faktory MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové proteiny MeSH
• NPM1 protein, human MeSH Prohlížeč
• nukleofosmin MeSH

Acute leukaemias are malignant diseases of haematopoiesis, traditionally classified according to the affected cell line as acute lymphoblastic and acute myelogenous leukaemia. In terms of incidence, acute leukaemias are rare diseases - in the Czech Republic, only 2-3 new acute myelogenous leukaemia cases/100 000 population are diagnosed annually and less than 1 new case of acute lymphoblastic leukaemia/100 000 residents. The causes of acute leukaemias are still poorly understood. The established risk factors are age, ionizing radiation or Downs syndrome. Moreover, a number of potential risk factors have been described to play a role in development of acute leukaemias and to multiply the risk, such as physical factors, chemicals, genetic and familial predispositions or other diseases. The presented review summarizes the knowledge of the aetiology of acute leukaemias published since 2000. It describes their epidemiological characteristics and risk factors and outlines the possibilities for their prevention.

• Klíčová slova
• acute lymphoblastic leukaemia, acute myelogenous leukaemia, acute myeloid leukaemia, doppler ultrasound of uterine artery, prevention, risk factors, treatment,
• MeSH
• akutní myeloidní leukemie * epidemiologie   etiologie   prevence a kontrola   MeSH
• incidence MeSH
• lidé MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

High BAALC gene expression has been associated with poor prognosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and has been suggested as a suitable marker for assessing minimal residual disease (MRD). The purpose of this study was to substantiate these findings by the analysis of a large data set of 632 diagnostic and follow-up samples in 142 intensively treated CN-AML patients. Paired diagnostic/relapse samples of 35 patients revealed stable high BAALC expression in 89%, irrespective of a high proportion of clonal evolution found in 49% of these cases. High BAALC expression, both directly after induction chemotherapy and within 3-6 months after induction chemotherapy, correlated significantly with shorter event-free survival and overall survival. Moreover, 8 of 10 patients displaying high BAALC expression levels after completion of induction therapy as well as 5 of 5 patients exhibiting high BAALC expression levels within 3-6 months after induction chemotherapy experienced relapse with a median of 197 and 101 days, respectively, from sampling to relapse. Thus, BAALC expression-based MRD detection during therapy may be considered a strategy to identify patients at high risk of relapse.

• Klíčová slova
• BAALC, acute myeloid leukaemia, gene expression, minimal residual disease, normal karyotype,
• MeSH
• akutní myeloidní leukemie diagnóza   mortalita   MeSH
• dospělí MeSH
• exprese genu MeSH
• hodnocení rizik metody   MeSH
• indukce remise MeSH
• karyotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové proteiny genetika   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• recidiva MeSH
• reziduální nádor diagnóza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie proveditelnosti MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BAALC protein, human MeSH Prohlížeč
• nádorové proteiny MeSH

BACKGROUND: Infectious complications during induction chemotherapy of acute myeloid leukaemia are very common. Prophylactic use of antibiotics however is an ongoing challenge in this situation due to bacterial multi-drug resistance. The aim of this study was to provide a comprehensive overview of the incidence of infectious complications in patients with AML undergoing induction therapy using the "7+3" protocol without routine antibiotic prophylaxis at one clinical site providing specialised haematological care in the Czech Republic, over a period of 15 years. The study also evaluates the aetiological spectrum of causative agents and the development of antibiotic resistance in the context of the use of the various classes of antibiotics. The analysis includes evaluation of the importance of risk factors for infectious complications and their impact on treatment of the underlying disease. The data are compared with published figures for similar cohorts of patients. PATIENTS AND METHODS: This study presents a retrospective analysis of infectious complications in 242 patients with acute myeloid leukaemia undergoing the first cycle of induction therapy without routine antibiotic prophylaxis in one clinical site in Czech Republic during years 2006-2020. RESULTS: A total of 363 febrile episodes (FE) were recorded. At least 1 FE during the induction was detected in 229 (94.6%) patients. Clinically defined infection was the cause in 96 (26.4%) FEs and blood stream infection in 69 (19.0%) FEs. Both complications occurred simultaneously in 29 (8.0%) FEs. 169 (46.6%) FEs were evaluated as fever of unknown origin (FUO). The achievement of complete remission had a significant effect on the duration of the FE (6 vs. 9 days, P=0.0005) and on the overall survival duration (79.3 vs. 6.5 months, P<0.0001). Patients diagnosed with infection or FUO at diagnosis were significantly more likely to suffer from colonisation by multi-drug resistant bacterial strains at discharge (29.2% vs. 16.3%, P=0.022). This group of patients used antibiotic therapy for a significantly longer time (35 vs. 23 days, P<0.0001). Infection was a contributing cause of death in 18 (7.4%) patients. Mortality was significantly related to the failure to achieve complete remission (P<0.0001). CONCLUSION: Infectious mortality during induction treatment without routine antibiotic prophylaxis was comparable to the published cohorts with prophylaxis. Regular microbiology surveillance with adequate initial antibiotic treatment can compensate routine antibiotic prophylaxis with slower development of antibiotic resistance.

• Klíčová slova
• acute myeloid leukaemia, antibiotic prophylaxis, antibiotic resistance, induction therapy, infectious complications, mortality,
• MeSH
• akutní myeloidní leukemie * komplikace   farmakoterapie   MeSH
• antibakteriální látky terapeutické užití   MeSH
• antibiotická profylaxe metody   MeSH
• lidé MeSH
• přehledová literatura jako téma MeSH
• retrospektivní studie MeSH
• sepse * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH

In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.

• Klíčová slova
• acute myeloid leukaemia, allogeneic haematopoietic cell transplantation, outcome, t(8;16)(p11;p13)/MYST3-CREBBP, whole-genome sequencing,
• MeSH
• abnormální karyotyp MeSH
• akutní myeloidní leukemie epidemiologie   genetika   terapie   MeSH
• analýza přežití MeSH
• chemoterapie konsolidační MeSH
• dospělí MeSH
• fúzní onkogenní proteiny genetika   MeSH
• indukce remise MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 16 ultrastruktura   MeSH
• lidské chromozomy, pár 8 ultrastruktura   MeSH
• mezinárodní spolupráce MeSH
• mladiství MeSH
• mutace MeSH
• myelodysplastické syndromy epidemiologie   MeSH
• následné studie MeSH
• přežití po terapii bez příznaků nemoci MeSH
• progrese nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• sekundární malignity chemicky indukované   epidemiologie   MeSH
• sekvenování celého genomu MeSH
• senioři MeSH
• translokace genetická * MeSH
• transplantace hematopoetických kmenových buněk MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH