Determination of IKZF1 gene deletions in children with B-cell acute lymphoblastic leukemia

Akutna limfoblastna levkemija (ALL), za katero je značilna maligna transformacija predniških celic B ali T limfocitov, je najpogostejša rakava bolezen pri otrocih. Sodobni načini zdravljenja omogočajo visoke stopnje preživetja, kljub temu pa imajo nekateri podtipi še vedno slabo prognozo. Raziskovalci se zato ukvarjajo s prepoznavanjem dodatnih (molekularno-genetskih) dejavnikov, ki vplivajo na neuspešno zdravljenje oz. ponovitev bolezni. V okviru magistrske naloge smo pri otrocih z B-celično ALL z metodo MLPA ovrednotili spremembe števila kopij nekaterih genov, povezanih z razvojem bolezni, in te spremembe povezali z izidi zdravljenja. Ugotovili smo, da so imeli otroci z delecijo gena IKZF1 in otroci z vsaj eno dodatno delecijo (IKZF1plus) slabše preživetje brez dogodka kot otroci brez tovrstnih genetskih sprememb. Otroci, razvrščeni v skupino IKZF1plus, so imeli tudi slabše celokupno preživetje. Metoda genetske analize, postavljena v tej nalogi, bo z uvedbo v diagnostiko omogočila prepoznavanje otrok z B-celično ALL, ki so bolj ogroženi, zaradi česar bodo ti otroci lahko deležni optimalnejšega zdravljenja.Acute lymphoblastic leukemia (ALL), characterized by malignant transformation of B- or T-cell precursors, is the most common cancer among children. While modern treatment protocols enable high survival rates, some subtypes are still associated with poor prognosis. Researchers are therefore working on recognition of additional (molecular-genetic) factors which affect treatment failure or disease recurrence. In our research, we used MLPA method to assess DNA copy-number alterations in children with B-cell ALL and linked these alterations to treatment outcome. We found out that children who harbour IKZF1 deletion and children with at least one additional deletion (IKZF1plus) had lower event-free survival compared to children without such genetic lesions. Children, classified as IKZF1plus, also had lower overall survival. Once this newly set-up genetic method is introduced into diagnostics, it will help recognize children with B-cell ALL at higher risk, who will then receive more optimal treatment

Clinical impacts of copy number variations in B-cell differentiation and cell cycle control genes in pediatric B-cell acute lymphoblastic leukemia

BACKGROUND: IKZF1 gene deletions have been identified as a poor prognostic factor in pediatric B-cell acute lymphoblastic leukemia (B-ALL), especially in the presence of co-occurring deletions (IKZF1(plus) profile). This study aimed to determine the frequency of IKZF1 deletions and deletions in other B-cell differentiation and cell cycle control genes, and their prognostic impact in Slovenian pediatric B-ALL patients. PATIENTS AND METHODS: We studied a cohort of 99 patients diagnosed with B-ALL from January 2012 to December 2020 and treated according to the ALL IC-BFM 2009 protocol. Eighty-eight bone marrow or peripheral blood samples were analysed for copy number variations (CNVs) using the SALSA MLPA P335 ALL-IKZF1 probemix. RESULTS: At least one CNV was detected in more than 65% of analysed samples. The most frequently altered genes were PAX5 and CDKN2A/B (30.7%, 26.1%, and 25.0%, respectively). Deletions in IKZF1 were present in 18.2% of analysed samples and were associated with an inferior 5-year event-free survival (EFS; 54.8% vs. 85.9%, p = 0.016). The IKZF1(plus) profile was identified in 12.5% of the analysed samples, and these patients had an inferior 5-year EFS than those with deletions in IKZF1 only and those without deletions (50.8% vs. 75.0% vs. 85.9%, respectively, p = 0.049). Overall survival (OS) was also worse in patients with the IKZF1(plus) profile than those with deletions in IKZF1 only and those without deletions (5-year OS 76.2% vs. 100% vs. 93.0%, respectively). However, the difference between the groups was not statistically significant. CONCLUSIONS: Our results are in concordance with the results obtained in larger cooperative clinical trials. Copy number variations analysis using the SALSA MLPA kit is a reliable tool for initial diagnostic approach in children with B-ALL, even in smaller institutions in low- and middle-income countries

Doprinos visokokvalitetnih valsartana liječenju arterijske hipertenzije i drugih bolesti već više od 15 godina

SUMMARY Valsartan is an angiotensin receptor antagonist used for the treatment of hypertension, heart failure, and post-myocardial infarction. It has demonstrated efficacy and safety, while also providing benefits beyond blood pressure control across broad patient populations with hypertension. Krka has been present in the markets with its valsartan for more than 15 years. During this time, we have built strong trust among physicians, pharmacists, and patients, which has enabled us to become the leading producer of valsartan in Europe (Central, Eastern, and South-Eastern European markets). Our valsartans, both monoform and single-pill combinations with a diuretic and/or calcium channel blocker and a statin, are recognized for their high quality and were not affected by recalls due to impurities issues in sartan-based products. They are therefore continously available in the markets without restriction. Moreover, our valsartans have also been acknowledged for their award-winning innovations and extensive international clinical evidence derived from both clinical trials and real-clinical practice, which is reflected in the trust of millions of patients with hypertension who control their blood pressure with Krka’s valsartans every day.Valsartan je antagonist receptora angiotenzina koji se uporabljuje za liječenje arterijske hipertenzije, zatajivanja srca i nakon infarkta miokarda. Iskazao je učinkovitost i sigurnost, a istodobno omogućio učinke šire od kontrole arterijskoga tlaka u različitim velikim populacijama hipertenzivnih bolesnika. Krka je svojim valsartanom prisutna na tržištima više od 15 godina. Tijekom tog razdoblja izgradili smo snažno povjerenje među liječnicima, ljekarnicima i bolesnicima, što je Krki omogućilo da postane vodeći proizvođač valsartana u Europi na tržištima srednje, istočne i južnoistočne Europe. Naši valsartani, i u monoobliku i u fiksnim kombinacijama s diuretikom i/ili blokatorom kalcijevih kanala i statinom, prepoznatljivi su po svojoj visokoj kvaliteti te na njih nisu utjecali opozivi zbog nečistoća u proizvodima na bazi sartana stoga su uvijek raspoloživi na tržištima bez ograničenja. Štoviše, spomenuti valsartani također su priznati zbog svojih nagrađenih inovacija i ekstenzivnih međunarodnih kliničkih dokaza dobivenih i u kliničkim ispitivanjima i u kliničkoj praksi, što se odražava u povjerenju milijuna hipertenzivnih bolesnika koji svoj arterijski tlak svakodnevno drže pod kontrolom Krkinim valsartanima