Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.

Background: Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence.

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hypermethylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripotent stem cells, and fetal brain were used as references.

Generation of a Zebrafish Knock-In Model Recapitulating Childhood ETV6::RUNX1-Positive B-Cell Precursor Acute Lymphoblastic Leukemia.

Approximately 25% of children with B-cell precursor acute lymphoblastic leukemia (pB-ALL) harbor the translocation, leading to the fusion gene. This translocation occurs in utero, but the disease is much less common than the prevalence of the fusion in newborns, suggesting that secondary mutations are required for overt leukemia. The role of these secondary mutations remains unclear and may contribute to treatment resistance and disease recurrence.

Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia.

Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics.

Dual direction associations between common autoimmune diseases and leukemia among children and young adults: A systematic review.

Background: Childhood leukemia and many autoimmune (AI) diseases are severe pediatric conditions with lifelong consequences. AI diseases form a heterogeneous disease group affecting about 5 % of children worldwide, while leukemia is the most common malignancy among children aged 0-14 years. The timing and similarities in suggested inflammatory and infectious triggers of AI disease and leukemia have raised a question whether the diseases share common etiological origins.

Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM.

Purpose: INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup of patients with improved outcomes on the basis of molecular profiling. The present analysis systematically investigates progression-free survival (PFS) and overall survival (OS) of patients receiving matching targeted treatment (MTT) with the most frequently applied drug classes and its correlation with underlying molecular alterations.

The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia.

Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM).

Characterization of the innate immune response to Streptococcus pneumoniae infection in zebrafish.

Streptococcus pneumoniae (pneumococcus) is one of the most frequent causes of pneumonia, sepsis and meningitis in humans, and an important cause of mortality among children and the elderly. We have previously reported the suitability of the zebrafish (Danio rerio) larval model for the study of the host-pathogen interactions in pneumococcal infection. In the present study, we characterized the zebrafish innate immune response to pneumococcus in detail through a whole-genome level transcriptome analysis and revealed a well-conserved response to this human pathogen in challenged larvae.

Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood -rearranged Acute Leukemia.

Infant acute lymphoblastic leukemia (ALL) with -gene rearrangements (-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with -r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in -r leukemia and included mutations in , , , , , , , and , with infants having fewer such mutations.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did.

Incidence trends of childhood central nervous system tumors in Finland 1990-2017.

Introduction: Central nervous system (CNS) tumors are a leading cause of cancer-related morbidity and mortality in children. Our aim is to characterize incidence trends of pediatric CNS tumors in Finland over the last three decades.

Methods: Data on all benign and malignant incident CNS tumors diagnosed in children aged 0-14 years in 1990-2017 were extracted from the Finnish Cancer Registry and classified according to the 2016 WHO classification of CNS tumors.

Successful eradication of chronic myeloid leukemia in a child despite allogeneic graft rejection.

Background: Chronic myeloid leukemia (CML) is a rare disease in children and treated with tyrosine kinase inhibitors (TKI) and with allogeneic hematopoietic stem cell transplantation (HSCT) still in many cases.

Case: We describe an 8-year-old patient with CML treated with two different TKIs before proceeding to allogeneic HSCT. Despite successful engraftment, prompt rejection of the graft was followed by autologous reconstitution.

Trends in ferritin measurements in children and adolescents: A Finnish 9-year observational study.

Aim: A lack of stored iron, indicated by low serum ferritin, has been associated with various clinical symptoms. There are no longitudinal data on the frequency of ferritin measurements in children and adolescents.

Methods: A total of 2834 children aged <18 years with serum ferritin and other anaemia-related blood parameters taken during an outpatient visit between 2012 and 2019 were investigated.

No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy.

Background: Patients with stage IV alveolar rhabdomyosarcoma (RMA) have a 5-year-survival rate not exceeding 30%. Here, we assess the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for these patients in comparison to standard-of-care regimens. We also compare the use of HLA-mismatched vs.

Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with no well-established prognostic biomarkers. We examined the expression of protein arginine methyltransferases across hematological malignancies and discovered high levels of mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated with the RNA and DNA processing and the T-ALL pathogenesis.

Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib.

Bioimpedance spinal needle provides high success and low complication rate in lumbar punctures of pediatric patients with acute lymphoblastic leukemia.

In this prospective single-arm study of 50 pediatric patients with acute lymphoblastic leukemia (ALL), we evaluated the clinical performance of a novel bioimpedance spinal needle system in 152 intrathecal treatment lumbar punctures (LP) of these patients. The system detects in real-time when the needle tip reaches the cerebrospinal fluid (CSF) in the spinal canal. The success was defined as getting a CSF sample and/or administering the intrathecal treatment with one needle insertion.

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.

Late adverse effects of childhood acute lymphoblastic leukemia treatment on developing dentition.

Background: Childhood cancer survivors show a variety of late adverse effects on dental health. The purpose of this study was to examine the prevalence and severity of dental abnormalities in permanent dentition in childhood leukemia survivors.

Materials And Methods: Retrospective analysis of panoramic radiographs was performed for 178 childhood leukemia survivors aged below 17 years at the time of diagnosis.

Expression of BCL6 in paediatric B-cell acute lymphoblastic leukaemia and association with prognosis.

B-cell lineage acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. Transcription factor B-cell lymphoma 6 (BCL6) is essential to germinal centre formation and antibody affinity maturation and plays a major role in mature B-cell malignancies. More recently, it was shown to act as a critical downstream regulator in pre-BCR+ B-ALL.

Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia.

The oncofetal protein insulin-like growth factor 2 mRNA-binding protein 3 () belongs to a family of RNA-binding proteins involved in localization, stability, and translational regulation of target RNAs. is used as a diagnostic and prognostic marker in several malignancies. Although the prognosis of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved, a subgroup of patients exhibits high-risk features and suffer from disease recurrence.