Patients with mixed lineage leukemia (MLL)-rearranged B-lymphoblastic leukemias (B-ALL) have an unfavorable prognosis and require intensified treatment. Multiple MLL fusion partners have been ...identified, complicating the diagnostic evaluation of MLL rearrangements. We analyzed molecular markers of MLL rearrangement for use in rapid diagnostic assays and found the immunomodulatory protein, Galectin-1 (Gal-1), to be selectively expressed in MLL-rearranged B-ALL.
Transcriptional profiling of ALL subtypes revealed selective overexpression of Gal-1 in MLL-rearranged ALLs. For this reason, we analyzed Gal-1 protein expression in MLL-germline and MLL-rearranged adult and infant pediatric B-ALLs and cell lines by immunoblotting, immunohistochemistry, and intracellular flow cytometry of viable tumor cell suspensions. Because deregulated gene expression in MLL-rearranged leukemias may be related to the altered histone methyltransferase activity of the MLL fusion protein complex, we also analyzed histone H3 lysine 79 (H3K79) dimethylation in the LGALS1 promoter region using chromatin immunoprecipitation.
Gal-1 transcripts were significantly more abundant in MLL-rearranged B-ALLs. All 32 primary MLL-rearranged B-ALLs exhibited abundant Gal-1 immunostaining, regardless of the translocation partner, whereas only 2 of 81 germline-MLL B-ALLs expressed Gal-1. In addition, Gal-1 was selectively detected in newly diagnosed MLL-rearranged B-ALLs by intracellular flow cytometry. The LGALS1 promoter H3K79 was significantly hypermethylated in MLL-rearranged B-ALLs compared with MLL-germline B-ALLs and normal pre-B cells.
In B-ALL, Gal-1 is a highly sensitive and specific biomarker of MLL rearrangement that is likely induced by a MLL-dependent epigenetic modification.
Immunophenotypic characterization of leukemic cells with the use of flow cytometry (FC) is a fundamental tool in acute lymphoblastic leukemia (ALL) diagnostics. A variety of genetic aberrations ...underlie specific B-cell precursor ALL (BCP-ALL) subtypes and their identification is of great importance for risk group stratification. These aberrations include: ETV6::RUNX1 fusion gene, Philadelphia chromosome (BCR::ABL1 fusion gene), rearrangements of the KMT2A, TCF3::PBX1 fusion gene and changes in chromosome number (hyperdiploidy and hypodiploidy). Diagnostic panels for BCP-ALL usually include B-cell lineage specific antigens: CD19, CD10, CD20, maturation stage markers: CD34, CD10, CD38, TdT, IgM and other markers useful for possible genetic subtype indication. Some genetic features of leukemic cells (blasts) are associated with expression of certain antigens. This review comprehensively summarizes all known research data on genotype-immunophenotype correlations in BCP-ALL. In some cases, single molecules are predictive of particular genetic subtypes, i.e., NG2 with KMT2A gene rearrangements or CD123 with hyperdiploidy. However, much more information on possible genotype or prognosis can be obtained with wider (≥8-color) panels. In several studies, a quantitative antigen expression scale and advanced statistical analyses were used to further increase the specificity and sensitivity of genotype/immunophenotype correlation detection. Fast detection of possible genotype/immunophenotype correlations makes multicolor flow cytometry an essential tool for initial leukemia diagnostics and stratification.
11q23/
MLL
rearrangements are frequently detected in pediatric acute myeloid leukemia. The analysis of their clinical significance is difficult because of the multitude of translocation fusion ...partners and their low frequency. The presence of t(10;11)(p12;q23) translocation was previously identified in pediatric acute myelogenous leukemia (AML). It is considered as the second most common translocation detected in pediatric 11q23/
MLL
-rearranged (present
KMT2A
) AML, after t(9;11)(p22;q23). The presence of the above translocation was previously identified as an unfavorable prognostic factor. Since June 2015, the Polish Pediatric Leukemia/Lymphoma Study Group has applied the therapeutic protocol requiring extensive diagnostics of genetic changes in pediatric AML. Until November 2019, molecular genetic studies were performed in 195 children with diagnosed AML to identify carriers of fusion gene transcripts for 28 most common chromosomal translocations in acute leukemia. The fusion gene transcript for translocation t(10;11)(p12;q23) involving
MLL
gene was detected with unexpectedly high frequency (8.9%) in our research. It was the highest frequency of all detected
MLL
rearrangements, as well as other detected fusion gene transcripts from chromosomal aberrations characteristic for AML. It seems that chromosomal aberration between chromosomes 10 and 11 can be relatively frequent in some populations. Paying attention to this fact and ensuring proper genetic diagnosis seem to be important for appropriate allocation of patients to risk groups of pediatric AML treatment protocols.
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•The pattern of whole CNAs associates with the kinetics of blasts clearance.•Aberrations of DNA repair genes may promote BCP-ALL chemoresistance.•Chromothripsis occurs in ‘’slow ...responders’’ harboring somatic defects of TP53 or RB1.
We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance A – early slow responders (n=105), B – patients with persistent leukemia (n=24), C – fast responders with the low but detectable disease at the end of induction (n=66) that corresponded with the patients’ clinical features, the microdeletion profile,the presence of gene fusions and patients survival. Low incidence of large CNAs and chromosomal numerical aberrations occurred in cluster A which included ALL samples showing recurrent microdeletions within the genes encoding transcription factors (i.e., IKZF1, PAX5, ETV6, and ERG), DNA repair genes (XRCC3 and TOX), or harboring chromothriptic pattern of CNAs. Low hyperdiploid karyotype with trisomy 8 or hypodiploidy was predominantly observed in cluster B. Whereas cluster C included almost exclusively high-hyperdiploid ALL samples with concomitant mutations in RAS pathway genes. The pattern of CNAs influences the kinetics of leukemic cell clearance and selected aberrations affecting DNA repair genes may contribute to BCP-ALL chemoresistance.
We aimed to identify miRNAs and pathways specifically deregulated in adolescent and young adult (AYA) T-ALL patients. Small RNA-seq showed no major differences between AYA and pediatric T-ALL, but it ...revealed downregulation of miR-143-3p in T-ALL patients. Prediction algorithms identified several known and putative oncogenes targeted by this miRNA, including KRAS, FGF1, and FGF9. Pathway analysis indicated signaling pathways related to cell growth and proliferation, including FGFR signaling and PI3K-AKT signaling, with the majority of genes overrepresented in these pathways being predicted targets of hsa-miR-143-3p. By luciferase reporter assays, we validated direct interactions of this miRNA with KRAS, FGF1 and FGF9. In cell proliferation assays, we showed reduction of cell growth upon miR-143-3p overexpression in two T-ALL cell lines. Our study is the first description of the miRNA transcriptome in AYA T-ALL patients and the first report on tumor suppressor potential of miR-143-3p in T-ALL. Downregulation of this miRNA in T-ALL patients might contribute to enhanced growth and viability of leukemic cells. We also discuss the potential role of miR-143-3p in FGFR signaling. Although this requires more extensive validation, it might be an interesting direction, since FGFR inhibition proved promising in preclinical studies in various cancers.
This article presents the results of measurements of the braking efficiency of vehicles adapted to be operated by drivers with motor dysfunctions. In such cars, the braking system is extended with an ...adaptive device that allows braking with the upper limb. This device applies pressure to the original brake in the car. The braking force and thus its efficiency depend on the mechanical ratio in the adapting device. In addition, braking performance depends on the sensitivity of the car’s original braking system and the maximum force that a disabled person can exert on the handbrake lever. Such a person may have limited power in the upper limbs. The force exerted by the driver can also be influenced by the position of the driver’s seat in relation to the handbrake lever. This article describes the research aimed at understanding the influence of the above-mentioned factors on the car braking performance. As a part of the analysis of the test results, a mathematical function was proposed that allows a parametric description of the braking efficiency index on the basis of data on the braking system, adaptation device, driver’s motor limitations, and the position of the driver’s seat. The information presented in this article can be used for the preliminary selection of adaptive devices to the needs of a given driver with a disability and to the vehicle construction.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently constitutes the leading and overwhelming health issue worldwide. In comparison ...with adults, children present milder symptoms, with most having an asymptomatic course. We hypothesized that COVID-19 infection has a negative impact on the continuation of chemotherapy and increases nonrelapse mortality.
This study was performed to assess the course of SARS-CoV-2 among children with hematological or oncological malignancies and its impact on cancer therapy. Records of SARS-CoV-2 infection in 155 children with malignancies from 14 Polish centers for pediatric hematology and oncology were collected and analyzed.
SARS-CoV-2 replication was observed in 155 patients. Forty-nine patients were symptomatic, with the following being the most common manifestations: fever (31 patients), gastrointestinal symptoms (10), coryza (13), cough (13) and headache (8). In children who were retested, the median time of a positive PCR result was 16 days (range 1-70 days), but 12.7% of patients were positive beyond day + 20. The length of viral PCR positivity correlated with the absolute neutrophil count at diagnosis. Seventy-six patients did not undergo further SARS-CoV-2 testing and were considered convalescents after completion of isolation. Antibiotic therapy was administered in 15 children, remdesivir in 6, convalescent plasma in 4, oxygen therapy in 3 (1-mechanical ventilation), steroids in 2, intravenous immunoglobulins in 2, and heparin in 4. Eighty patients were treated with chemotherapy within 30 days after SARS-CoV-2 infection diagnosis or were diagnosed with SARS-CoV-2 infection during 30 days of chemotherapy administration. Respiratory symptoms associated with COVID-19 and associated with oxygen therapy were present in 4 patients in the study population, and four deaths were recorded (2 due to COVID-19 and 2 due to progressive malignancy). The probability of 100-day overall survival was 97.3% (95% CI 92.9-99%). Delay in the next chemotherapy cycle occurred in 91 of 156 cases, with a median of 14 days (range 2-105 days).
For the majority of pediatric cancer patients, SARS-CoV-2 infection does not result in a severe, life-threatening course. Our data show that interruptions in therapy are common and can result in suboptimal therapy.
"Managing Undernutrition in Pediatric Oncology" is a collaborative consensus statement of the Polish Society for Clinical Nutrition of Children and the Polish Society of Pediatric Oncology and ...Hematology. The early identification and accurate management of malnutrition in children receiving anticancer treatment are crucial components to integrate into comprehensive medical care. Given the scarcity of high-quality literature on this topic, a consensus statement process was chosen over other approaches, such as guidelines, to provide comprehensive recommendations. Nevertheless, an extensive literature review using the PubMed database was conducted. The following terms, namely pediatric, childhood, cancer, pediatric oncology, malnutrition, undernutrition, refeeding syndrome, nutritional support, and nutrition, were used. The consensus was reached through the Delphi method. Comprehensive recommendations aim to identify malnutrition early in children with cancer and optimize nutritional interventions in this group. The statement underscores the importance of baseline and ongoing assessments of nutritional status and the identification of the risk factors for malnutrition development, and it presents tools that can be used to achieve these goals. This consensus statement establishes a standardized approach to nutritional support, aiming to optimize outcomes in pediatric cancer patients.
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