Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, yet its etiology remains incompletely understood. However, over the course of three waves of germline genetic research, several non-environmental causes have been identified. Beginning with trisomy 21, seven overt cancer predisposition syndromes (CPSs)-characterized by broad clinical phenotypes that include an elevated risk of pALL-were first described. More recently, newly described CPSs conferring high risk of pALL are increasingly covert, with six exhibiting only minimal or no non-cancer features. These 13 CPSs now represent the principal known hereditary causes of pALL, and human pangenomic data indicates a strong negative selection against mutations in the genes associated with these conditions. Collectively they affect approximately 1 in 450 newborns, of which just a minority will develop the disease. As evidenced by tailored leukemia care protocols for children with trisomy 21, there is growing recognition that CPSs warrant specialized diagnostic, therapeutic, and long-term management strategies. In this review, we investigate the evidence that the 12 other CPSs associated with high risk of pALL may also see benefits from specialized care - even if these needs are often incompletely mapped or addressed in the clinic. Given the rarity of each syndrome, collaborative international research and shared data initiatives will be crucial for advancing knowledge and improving outcomes for these patients.
Adolescent and young adults (AYAs) with chronic myeloid leukemia in chronic phase (CML-CP) reportedly respond worse to tyrosine kinase inhibitors (TKIs) than adults, potentially due to additional genetic abnormalities, including mutations in cancer-related genes (CRGs). This real-life study compared mutation profiles and their impact on outcomes in 80 AYA, 97 adult, and 16 pediatric CML-CP patients, alongside 81 BCR::ABL1-positive acute lymphoblastic leukemia (Ph+ ALL) patients. CRG mutations were more frequent in AYAs (25.0%) than in adults (19.6%) or children (12.5%). AYAs with Ph+ ALL exhibited higher mutational frequencies (53.3%) compared to children (26.7%) and adults (38.9%). At diagnosis, mutations in ASXL1, DNMT3A, and TET2 dominated in CML-CP and RUNX1, IKZF1, and BCR::ABL1 in Ph+ ALL. ASXL1 mutations correlated with reduced progression-free survival (PFS) in AYAs and adults. Unlike adults, AYAs showed no increase in BCR::ABL1 kinase domain mutations during TKI therapy. Nilotinib improved PFS in AYAs with ASXL1 mutations, highlighting the efficacy of higher-generation TKIs. ASXL1 mutations also impaired erythropoiesis, warranting further validation. Despite a higher mutational burden, AYAs did not exhibit worse prognoses than adults. Lower mutation rates at follow-up suggest potential impact of nilotinib. Mutation profiling and optimized TKI use are crucial to mitigate progression risks in CRG-mutated patients.
- Publikační typ
- časopisecké články MeSH
Monitoring of minimal residual disease (MRD) after hematopoietic stem cell transplantation (HSCT) in patients with acute lymphoblastic leukemia (ALL) is vital for timely therapeutic intervention planning. However, interpreting low-positive results from the current standard method, quantitative PCR (qPCR) of immunoglobulin and T-cell receptor gene rearrangements (IG/TR), poses challenges due to the risk of false positivity caused by non-specific amplification. We aimed to improve MRD detection specificity using the next-generation amplicon sequencing (NGS) of IG/TR rearrangements for better relapse prediction. In pediatric and young adult ALL patients undergoing sequential post-HSCT MRD monitoring, we prospectively re-tested positive non-quantifiable qPCR results with NGS-MRD using the EuroClonality-NGS approach. We were able to confirm 13 out of 47 (27.7%) qPCR positive results using the more specific NGS-MRD method. Out of 10 patients with at least one MRD positivity confirmed by NGS, six relapsed (60%) 1-3.7 months after testing. Among 25 patients with all NGS-MRD results negative, two relapses occurred (8%) after 5.1 and 12.1 months. One-year RFS was 40% versus 96% and 3-year OS was 33.3% versus 94.4% for the NGS-positive and NGS-negative groups, respectively. The difference was not attributable to a varying rate of therapeutic interventions. Six patients out of 14 who had immunosuppressive treatment tapered or received donor lymphocyte infusion in response to MRD positivity developed significant graft versus host disease, leading to one fatality. This underscores the importance of enhancing the post-HSCT relapse risk prediction accuracy through NGS-MRD testing to avoid unnecessary interventions.
- Publikační typ
- časopisecké články MeSH
Can peripheral blood be used to detect residual disease in acute lymphoblastic leukaemia (ALL) when we increase the sensitivity of the method used? Bendig et al. found that a larger amount of material and the use of next-generation sequencing (NGS) detects MRD in peripheral blood in up to half of patients with B-cell precursor ALL (BCP-ALL) where routine examination was negative. However, a negative result does not exclude the presence of residual disease and thus still limits the use of peripheral blood. Commentary on: Bendig et al. Next-generation sequencing and high DNA input identify previously missed measurable residual disease in peripheral blood of B-cell precursor acute lymphoblastic leukaemia. Br J Haematol 2025; 206:353-356.
- Klíčová slova
- ALL, peripheral blood, residual disease,
- MeSH
- akutní lymfatická leukemie * krev diagnóza genetika MeSH
- lidé MeSH
- reziduální nádor * diagnóza krev MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.
- MeSH
- akutní lymfatická leukemie farmakoterapie metabolismus patologie MeSH
- asparaginasa * farmakologie metabolismus MeSH
- citrátový cyklus účinky léků MeSH
- glutamin metabolismus MeSH
- glutathion * metabolismus MeSH
- kyselina glutamová * metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protinádorové látky farmakologie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- asparaginasa * MeSH
- glutamin MeSH
- glutathion * MeSH
- kyselina glutamová * MeSH
- protinádorové látky MeSH
Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.
- MeSH
- adaptorové proteiny signální transdukční * genetika metabolismus MeSH
- dítě MeSH
- genová přestavba MeSH
- kojenec MeSH
- lidé MeSH
- lymfoblastická leukemie-lymfom z prekurzorových T-buněk genetika patologie MeSH
- předškolní dítě MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- proteiny s doménou LIM * genetika MeSH
- protoonkogenní proteiny MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adaptorové proteiny signální transdukční * MeSH
- LMO2 protein, human MeSH Prohlížeč
- proteiny buněčného cyklu MeSH
- proteiny s doménou LIM * MeSH
- protoonkogenní proteiny MeSH
BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
- Klíčová slova
- ABL1, Acute lymphoblastic leukemia, BCR, Chronic myeloid leukemia, Genomic breakpoints,
- MeSH
- akutní lymfatická leukemie * genetika patologie MeSH
- bcr-abl fúzní proteiny * genetika MeSH
- body zlomu chromozomu * MeSH
- chronická myeloidní leukemie * genetika patologie MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- Názvy látek
- bcr-abl fúzní proteiny * MeSH
