• Klíčová slova
• syndrom VEXAS, gen UBA1,
• MeSH
• cytogenetické vyšetření MeSH
• genetické nemoci vázané na chromozom X diagnóza   farmakoterapie   genetika   MeSH
• inhibitory interleukinu terapeutické užití   MeSH
• klonální hematopoéza * MeSH
• lidé MeSH
• mutace genetika   MeSH
• myelodysplastické syndromy * diagnóza   farmakoterapie   genetika   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• Check Tag
• lidé MeSH

Klonální hematopoéza neurčitého potenciálu (clonal hematopoiesis of indeterminate potential; CHIP) nástává během stárnutí lidského organizmu postupnou kumulací somatických a potenciálně preleukemických mutací v hematopoetických kmenových buňkách. Tyto mutace se vyskytují v genech, které mimo jiné hrají důležitou roli v regulaci zánětu. Riziko hematologické malignity u nositelů CHIP mutací je relativně nízké. U těchto pacientů se však vyskytuje 40% riziko celkové mortality způsobené vyšším výskytem infarktu myokardu a CMP. Ačkoli v současnosti přibývají důkazy o vztahu mezi CHIP, zánětem a kardiovaskulárními chorobami, vztah mezi CHIP a CMP dosud nebyl zcela objasněn. Cílem tohoto přehledného referátu je poukázat na aktuální a potenciálně klinicky relevatní problematiku, která je nepochybně výchozí pro další výzkum.

Clonal hematopoiesis of indeterminate potential (CHIP) occurs during human aging through the progressive accumulation of somatic and potentially preleukemic mutations in hematopoietic stem cells. These mutations occur in genes that, among other things, play an important role in the regulation of inflammation. The risk of hematological malignancy in carriers of CHIP mutations is relatively low. However, these patients have a 40% risk of all-cause mortality due to a higher incidence of myocardial infarction and stroke. Although there is recent evidence of a relationship between CHIP, inflammation and cardiovascular diseases, the relationship between CHIP and stroke has not yet been fully elucidated. The aim of this review is to highlight a timely and potentially clinically relevant issue that is undoubtedly a starting point for further research.

• MeSH
• ateroskleróza etiologie   genetika   komplikace   MeSH
• cévní mozková příhoda * etiologie   genetika   komplikace   MeSH
• kardiovaskulární nemoci etiologie   genetika   komplikace   MeSH
• klinická studie jako téma MeSH
• klonální hematopoéza * genetika   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

• MeSH
• dospělí MeSH
• geny p16 MeSH
• klonální evoluce genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• lymfom z plášťových buněk * diagnóza   farmakoterapie   genetika   MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mutace v genu TP53 představují nejdůležitější nepříznivý prognostický a prediktivní faktor u pacientů s chronickou lymfocytární leukemií (CLL) a přispívají k celkově horšímu průběhu onemocnění a riziku časného relapsu či rezistenci na podávanou chemoimunoterapii. Z dosavadních výsledků vyplývá, že při léčbě chemoimunoterapií (fludarabin, cyklofosfamid a rituximab – FCR) v první linii dochází ke klonální selekci TP53 aberantních buněk, což má nepříznivý vliv na prognózu onemocnění. Recentní studie zabývající se klonální evolucí mutací v genu TP53 pod vlivem terapie BCR a Bcl-2 inhibitorovými léčivy podobný trend nenaznačují. V klinické diagnostice aberací TP53 se čím dál více využívá metody sekvenování nové generace (NGS), které dosahují citlivosti detekce alelické frekvence pod 10 % oproti standardně zavedenému Sangerovu sekvenování. V posledních letech se pozornost výzkumu CLL upíná zejména k mutacím v genu TP53 s alelickou frekvencí pod 10 % a jejich klinickou významnost. V následujícím přehledovém článku shrnujeme doposud publikované výsledky klonální evoluce mutací v genu TP53 pod vlivem různým terapeutických režimů zejména s ohledem na mutace s alelickou četností < 10 % a jejich klinickou interpretaci.

TP53 gene mutations represent the most important adverse prognostic and predictive factor in patients with chronic lymphocytic leukaemia (CLL) and contribute to an overall worse disease course and risk of early relapse or resistance to chemoimmunotherapy. Results to date suggest that first-line chemoimmunotherapy (FCR) results in clonal selection of TP53 aberrant cells, which has an adverse effect on disease prognosis. Recent studies investigating the clonal evolution of TP53 mutations under BCR and Bcl-2 inhibitor therapy do not suggest a similar trend. Next-generation sequencing (NGS) methods are being increasingly used in the clinical diagnosis of TP53 aberrations, achieving sensitivity of allelic frequency detection below 10% compared to standard Sanger sequencing. In recent years, the focus of CLL research has been on TP53 gene mutations with allelic frequencies below 10% and their clinical significance. In the following review article, we summarize the results published so far on the clonal evolution of TP53 gene mutations under different therapeutic regimens, especially with respect to mutations with an allelic frequency < 10% and their clinical interpretation.

• MeSH
• chronická lymfatická leukemie * farmakoterapie   genetika   terapie   MeSH
• frekvence genu účinky léků   MeSH
• geny p53 * účinky léků   MeSH
• klinická studie jako téma MeSH
• klonální evoluce účinky léků   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• mutace účinky léků   MeSH
• výsledek terapie MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy-related myeloid neoplasms (t-MN). Using target next-generation sequencing (t-NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t-MN after treatment with chemo-(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t-MN (77%, median number of variants for patient: 2, range 0-6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP-variant at the time of t-MN (median: 2, range: 1-5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population-based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t-MN, compared to the population-based cohort (5/8, 62.5% vs. 34/285, 12%, p = 0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo-free therapies in CHIP-positive cases.

• MeSH
• chronická lymfatická leukemie * farmakoterapie   genetika   patologie   MeSH
• klonální hematopoéza genetika   MeSH
• lidé MeSH
• mutace MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• rizikové faktory MeSH
• sekundární malignity * etiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved. METHODS: We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity. RESULTS: At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P = 0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NFκB (P = 0.04, P = 0.01, and P = 0.02, respectively). CONCLUSIONS: Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort.

• MeSH
• chronická lymfatická leukemie genetika   MeSH
• klonální evoluce genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   MeSH
• protoonkogenní proteiny c-bcr metabolismus   MeSH
• signální transdukce MeSH
• telomerasa genetika   MeSH
• telomery ultrastruktura   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Patients with chronic lymphocytic leukemia (CLL) bearing TP53 mutations experience chemorefractory disease and are therefore candidates for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter for debate. Herein, we describe clonal evolution scenarios of low-burden TP53 mutations, the clinical impact of which we analyzed in a "real-world" CLL cohort. TP53 status was assessed by targeted next-generation sequencing (NGS) in 511 patients entering first-line treatment with chemo- and/or immunotherapy and 159 patients in relapse before treatment with targeted agents. Within the pretherapy cohort, 16% of patients carried low-burden TP53 mutations (0.1% to 10% VAF). Although their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). In a subgroup with TP53 mutations of 1% to 10% VAF, the impact on OS was observed only in patients with unmutated IGHV who had not received targeted therapy, as patients benefited from switching to targeted agents, regardless of initial TP53 mutational status. Analysis of the clonal evolution of low-burden TP53 mutations showed that the highest expansion rates were associated with fludarabine, cyclophosphamide, and rituximab regimen in both first- and second-line treatments (median VAF increase, 14.8× and 11.8×, respectively) in contrast to treatment with less intense treatment regimens (1.6×) and no treatment (0.8×). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). Sporadic cases of TP53 mutations' clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53 variants in clinical decision making.

• MeSH
• chronická lymfatická leukemie genetika   terapie   MeSH
• dospělí MeSH
• imunoterapie MeSH
• Kaplanův-Meierův odhad MeSH
• klonální evoluce * účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace účinky léků   MeSH
• nádorové buňky kultivované MeSH
• nádorový supresorový protein p53 genetika   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   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
• časopisecké články MeSH
• práce podpořená grantem MeSH

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

• MeSH
• analýza jednotlivých buněk MeSH
• buňky kostní dřeně metabolismus   MeSH
• dítě MeSH
• HEK293 buňky MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• Kaplanův-Meierův odhad MeSH
• klonální evoluce genetika   MeSH
• klonální hematopoéza genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• myelodysplastické syndromy genetika   patologie   MeSH
• nádorové supresorové proteiny genetika   MeSH
• předškolní dítě MeSH
• transkripční faktor GATA2 genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Ag-inexperienced memory-like T (AIMT) cells are functionally unique T cells, representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and an unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multiomics approaches, including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice, independent of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Cohousing with feral mice changed the bacterial colonization of laboratory strains but had only minimal effects on the CD8+ T cell compartment, including AIMT cells.

• MeSH
• antigeny genetika   imunologie   MeSH
• fenotyp MeSH
• imunologická paměť genetika   imunologie   MeSH
• klonální evoluce MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• nestabilita genomu MeSH
• stárnutí genetika   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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.

• 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
• protokoly protinádorové 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