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Approximately 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is a P53-activating mechanism via MDM2 inhibition by ribosomal protein L11 (RPL11). We analyzed the role of the nucleolar stress response using BCP-ALL cell lines and patient samples by drug sensitivity tests, Western blotting, and reverse transcription polymerase chain reaction. We revealed that the nucleolar stress response works properly in TP53 wild-type human BCP-ALL cell lines. Next, we found that 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine had anti-leukemic effects via the nucleolar stress response within BCP-ALL treatment. Comparing the samples at onset and relapse in children with BCP-ALL, RPL11 mRNA expression decreased at relapse in seven of nine cases. Furthermore, leukemia cells with relapse acquired resistance to these four drugs and suppressed P53 and RPL11 expression. Our findings suggest that the nucleolar stress response is a novel anti-leukemia mechanism in BCP-ALL. As these four drugs are key therapeutics for BCP-ALL treatment, dysfunction of the nucleolar stress response may be related to clinical relapse or refractoriness. Nucleolar stress response may be a target to predict and improve the chemotherapy effect for pediatric BCP-ALL.

Leukemia is the most common type of cancer in children. Today, many children can be cured if they receive full treatment on time. However, in some places, children do not finish their treatment. This is called “treatment abandonment,” and it is one of the main reasons why children die of leukemia in low- and middle-income countries. In this study, we followed 574 children under 18 years old with leukemia in Oaxaca, Puebla, and Tlaxcala between 2021 and 2023. We looked at two main factors: how far families live from the hospital and their socioeconomic situation, including whether they had public health insurance. We measured the distance from the children’s homes to the hospitals and collected information about parents’ education, work, and family size. We found that about 17 out of every 100 children (16.6%) abandoned their treatment. Two main reasons explained this: not having public health insurance and living far away from the hospital. Children without health insurance were almost three times more likely to stop treatment, and those living more than 141 kilometers away were about 1.7 times more likely to abandon it. Other family factors, such as the number of siblings or parents’ education level, did not have a strong impact. These results show that distance and lack of insurance are the biggest barriers to completing leukemia treatment in this region of Mexico. To save more lives, it is important to expand access to health insurance, reduce the hidden costs of care, and find ways to support families who live far from hospitals.

Chronic myeloid leukemia (CML) rarely presents under 15 years of age, and its incidence is as low as 2% of all leukemia. Ophthalmic manifestations often present either initially with the diagnosis or as a sign of relapse after remission. The recommended treatment is systemic chemotherapy, intrathecal chemotherapy, ocular irradiation, and/or intravitreal methotrexate. Herein, we report a 13-year-old child with a history of CML and central nervous system relapse under remission currently. He presented to us with bilateral ophthalmic relapse. He was treated with ocular irradiation and intrathecal chemotherapy. On follow-up, the ophthalmic infiltration showed resolution, which was also seen on multimodal imaging.

Progress in the care of the hematologic malignancies of childhoond has been one of the proudest success stories in modern pediatrics. The cure rates of these diseases have improved from essentially zero in the 1950’s and early 1960’s to cure rates that range from 65%–90% in modern centers. While the largest improvements have been made in the most common (and the lower risk subtypes) of Acute Lymphoblastic Leukemia (ALL), there has also been significant progress in both the higher risk forms of ALL (i.e. Philadelphia chromosome positive, Ph+ ALL) and in Acute Myeloid Leukemia (AML). This progress has been achieved by the careful and stepwise identification of clinical, cytogenetic, molecular, and most recently response-based prognostic criteria, that now allow oncologists to focus the intensity of the therapy more closely to what is required to cure individual subgroups of patients. Conclusion Pediatricians need to be familiar with the changes in diagnostic and therapeutic approaches, because these changes have impact on: the laboratory tests that should be ordered at the time of specialist referral; counseling of patients and their families; and with the advent of “shared care models” pediatricians will need to be more involved in the general, supportive, and long-term care of these patients.

Prophylactic or therapeutic antibiotic use along with chemotherapy treatment potentially has a long-standing adverse effect on the resident gut microbiota. We have established a case-control cohort of 32 pediatric and adolescent acute lymphoblastic leukemia (ALL) patients and 25 healthy siblings (sibling controls) to assess the effect of chemotherapy as well as antibiotic prophylaxis on the gut microbiota. We observe that the microbiota diversity and richness of the ALL group is significantly lower than that of the control group at diagnosis and during chemotherapy. The microbiota diversity is even lower in antibiotics-exposed ALL patients. Although the gut microbial diversity tends to stabilize after 1-year post-chemotherapy, their abundances were altered because of chemotherapy and prophylactic antibiotic treatments. Specifically, the abundances of mucolytic gram-positive anaerobic bacteria, including Ruminococcus gnavus and Ruminococcus torques, tended to increase during the chemotherapy regimen and continued to be elevated 1 year beyond the initiation of chemotherapy. This dysbiosis may contribute to the development of gastrointestinal complications in ALL children following chemotherapy. These findings set the stage to further understand the role of the gut microbiome dynamics in ALL patients and their potential role in alleviating some of the adverse side effects of chemotherapy and antibiotics use in immunocompromised children.

Background Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero , when global redistribution of DNA methylation occurs driving tissue differentiation. Methods Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. Results The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues ( n =5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression ( n =2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. Conclusion This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. Key points • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.

Mitochondria are critical for cellular energy, and while large deletions in their genome (mtDNA) are linked to primary mitochondrial diseases, their significance in cancer is less understood. Given cancer’s metabolic nature, investigating mtDNA deletions in tumors at various stages could provide insights into disease origins and treatment responses. In this study, we analyzed 148 bone marrow samples from 129 pediatric patients with B-cell (B-ALL) and T-cell (T-ALL) acute lymphoblastic leukemia at diagnosis, remission, and relapse using long-range PCR, next-generation sequencing, and the Splice-Break2 pipeline. Both T-ALL and B-ALL exhibited significantly more mtDNA deletions than did the controls, with T-ALL showing a ~100-fold increase and B-ALL a ~15-fold increase. The T-ALL samples also exhibited larger deletions (median size > 2000 bp) and greater heterogeneity, suggesting increased mitochondrial instability. Clustering analysis revealed distinct deletion profiles between ALL subtypes and across disease stages. Notably, large clonal deletions were detected in some B-ALL remission samples, including one affecting up to 88% of mtDNA molecules, which points toward treatment-driven selection or toxicity. A multivariate analysis confirmed that disease type, timepoint, and WHO subtype significantly influenced mtDNA deletion metrics, while age and gender did not. These findings suggest that mtDNA deletion profiling could serve as a biomarker for pediatric ALL and may indicate mitochondrial toxicity contributing to late effects in survivors.

RNA molecules are a source of phenotypic diversity and an operating system that connects multiple genetic and metabolic processes in the cell. A dysregulated RNA network is a common feature of cancer. Aberrant expression of long non-coding RNA (lncRNA), micro RNA (miRNA), and circular RNA (circRNA) in tumors compared to their normal counterparts, as well as the recurrent mutations in functional regulatory cis-acting RNA motifs have emerged as biomarkers of disease development and progression, opening avenues for the design of novel therapeutic approaches. This review looks at the progress, challenges and future prospects of targeting cis-acting and trans-acting RNA elements for leukemia diagnosis and treatment.

Background Refractory central nervous system (CNS) involvement is among the major causes of therapy failure in childhood acute leukemia. Applying contemporary diagnostic methods, CNS disease is often underdiagnosed. To explore more sensitive and less invasive CNS status indicators, we examined microRNA (miR) expressions and extracellular vesicle (EV) characteristics. Methods In an acute lymphoblastic leukemia (ALL) discovery cohort, 47 miRs were screened using Custom TaqMan Advanced Low-Density Array gene expression cards. As a validation step, a candidate miR family was further scrutinized with TaqMan Advanced miRNA Assays on serial cerebrospinal fluid (CSF), bone marrow (BM) and peripheral blood samples with different acute leukemia subtypes. Furthermore, small EV-rich fractions were isolated from CSF and the samples were processed for immunoelectron microscopy with anti-CD63 and anti-CD81 antibodies, simultaneously. Results Regarding the discovery study, principal component analysis identified the role of miR-181-family (miR-181a-5p, miR-181b-5p, miR-181c-5p) in clustering CNS-positive (CNS + ) and CNS-negative (CNS ‒ ) CSF samples. We were able to validate miR-181a expression differences: it was about 52 times higher in CSF samples of CNS + ALL patients compared to CNS ‒ cases (n = 8 vs. n = 10, ΔFC = 52.30, p = 1.5E−4), and CNS + precursor B cell subgroup also had ninefold higher miR-181a levels in their BM (p = 0.04). The sensitivity of CSF miR-181a measurement in ALL highly exceeded those of conventional cytospin in the initial diagnosis of CNS leukemia (90% vs. 54.5%). Pellet resulting from ultracentrifugation of CNS + CSF samples of ALL patients showed atypical CD63 − /CD81 − small EVs in high density by immunoelectron microscopy. Conclusions After validating in extensive cohorts, quantification of miR-181a or a specific EV subtype might provide novel tools to monitor CNS disease course and further adjust CNS-directed therapy in pediatric ALL.

Background An estimated 15,000 children and adolescents under the age of 19 years are diagnosed with leukemia, lymphoma and other tumors in the USA every year. All children and adolescent acute leukemia patients will undergo chemotherapy as part of their treatment regimen. Fortunately, survival rates for most pediatric cancers have improved at a remarkable pace over the past three decades, and the overall survival rate is greater than 90 % today. However, significant differences in survival rate have been found in different age groups (94 % in 1–9.99 years, 82 % in ≥10 years and 76 % in ≥15 years). ALL accounts for about three out of four cases of childhood leukemia. Intensive chemotherapy treatment coupled with prophylactic or therapeutic antibiotic use could potentially have a long-term effect on the resident gastrointestinal (GI) microbiome. The composition of GI microbiome and its changes upon chemotherapy in pediatric and adolescent leukemia patients is poorly understood. In this study, using 16S rRNA marker gene sequences we profile the GI microbial communities of pediatric and adolescent acute leukemia patients before and after chemotherapy treatment and compare with the microbiota of their healthy siblings. Results Our study cohort consisted of 51 participants, made up of matched pediatric and adolescent patients with ALL and a healthy sibling. We elucidated and compared the GI microbiota profiles of patients and their healthy sibling controls via analysis of 16S rRNA gene sequencing data. We assessed the GI microbiota composition in pediatric and adolescent patients with ALL during the course of chemotherapy by comparing stool samples taken before chemotherapy with stool samples collected at varying time points during the chemotherapeutic treatment. The microbiota profiles of both patients and control sibling groups are dominated by members of Bacteroides , Prevotella , and Faecalibacterium . At the genus level, both groups share many taxa in common, but the microbiota diversity of the patient group is significantly lower than that of the control group. It was possible to distinguish between the patient and control groups based on their microbiota profiles. The top taxa include Anaerostipes , Coprococcus , Roseburia , and Ruminococcus2 with relatively higher abundance in the control group. The observed microbiota changes are likely the result of several factors including a direct influence of therapeutic compounds on the gut flora and an indirect effect of chemotherapy on the immune system, which, in turn, affects the microbiota. Conclusions This study provides significant information on GI microbiota populations in immunocompromised children and opens up the potential for developing novel diagnostics based on stool tests and therapies to improve the dysbiotic condition of the microbiota at the time of diagnosis and in the earliest stages of chemotherapy.