Publications
2026
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The Childhood Cancer and Leukemia International Consortium (CLIC): Expanding global collaboration in pediatric cancer etiology research
Childhood cancers are rare, but incidence has risen modestly in countries with robust registration, partly reflecting improved diagnosis. In high-income countries, cancer is the leading cause of disease-related death in children. Marked inequities in incidence, survival, and research capacity underscore the need for large-scale collaboration to identify environmental, genetic, and contextual determinants of risk. The Childhood Cancer and Leukemia International Consortium (CLIC) was established... -
Co-occurrence of acute leukemia and type 1 diabetes among children: a caseseries
CONCLUSION: This case-series presents findings, which align with previous observations (e.g., Down syndrome, pancreatitis), though a less often reported finding, Sotos syndrome, was also observed. -
Association of Childhood Acute Leukemia With Autoimmune Diseases
Emerging evidence indicates a possible association between acute leukemia and type 1 diabetes mellitus (T1DM). However, the relationship between acute leukemia and other autoimmune diseases (AIDs) remains less well understood. To address this gap, we conducted a case-control study using detailed Finnish register-based data. We identified 1626 childhood leukemia cases (diagnosed 1990-2019) from the Finnish Cancer Registry and sampled three age- and sex-matched controls per case. Information on 29... -
Intensive chemotherapy for high-risk acute lymphoblastic leukemia in first remission: results from the NOPHO ALL2008 study
No abstract -
Childhood acute leukemia and type 1 diabetes in children: A nationwide case-control study
Etiology of childhood acute leukemia is largely unknown, though environmental factors and infection-related immune responses may contribute. Type 1 diabetes mellitus (T1DM), an autoimmune disease also with onset primarily in childhood, shares risk factors with leukemia, including childhood infection patterns. Epidemiological evidence suggests a link between T1DM and leukemia, but the extent of this association remains unclear. We identified 1626 leukemia cases diagnosed under 18 years of age...
2025
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Clustering patterns in Finnish type 1 diabetes patients: a nationwide register-based study
CONCLUSIONS: These results demonstrate evidence of spatiotemporal clustering of T1DM in Finnish children, supporting the hypothesis of environmental triggers in T1DM etiology. These findings highlight the need for further research to identify the specific environmental factors and mechanisms behind the clustering. -
Intensive chemotherapy for high-risk acute lymphoblastic leukemia in first remission: results from the NOPHO ALL2008 study
No abstract -
Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM
Diffuse midline glioma (DMG; a subtype of pediatric high-grade glioma) is a fatal disease in children, due to the localization in critical structures of the central nervous system, its invasive nature, and limited treatment options. Molecularly, DMG with loss of histone 3 K27 trimethylation (mostly through the typical K27M-mutation in histone 3) have been relatively well characterized, however, no unambiguous Achilles' heel for targeted therapeutic approaches could be identified to date. This... -
The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia
To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months,... -
Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data
Recent advances in ultra-low coverage whole-genome sequencing (WGS) of single cells have enabled detailed analysis of copy number variation at a throughput approaching that of single-cell RNA sequencing. However, downstream computational methods have not seen comparable advances and are largely adaptations of deep sequencing methodology with reduced precision. Here, we present ASCENT, a computational method built to take full advantage of modern direct tagmentation-based WGS at ultra-low depth.... -
Published Population Pharmacokinetic Models of Imatinib Perform Poorly on TDM Data from Pediatric Patients
CONCLUSIONS: Current models fail to accurately predict imatinib plasma concentrations in our real-world dataset, especially for children. Future pharmacokinetic studies should focus on developing better models for pediatric populations. -
Childhood acute leukemia and type 1 diabetes in children: A nationwide case-control study
Etiology of childhood acute leukemia is largely unknown, though environmental factors and infection-related immune responses may contribute. Type 1 diabetes mellitus (T1DM), an autoimmune disease also with onset primarily in childhood, shares risk factors with leukemia, including childhood infection patterns. Epidemiological evidence suggests a link between T1DM and leukemia, but the extent of this association remains unclear. We identified 1626 leukemia cases diagnosed under 18 years of age... -
Genomic determinants of therapy response in ETV6::RUNX1 leukemia
ETV6::RUNX1 leukemia is the second most common subtype of childhood B cell acute lymphoblastic leukemia (B-ALL). Although it generally has a low relapse risk, a significant proportion of B-ALL relapses occur within this subtype due to its relatively high incidence. Measurable residual disease at the end of induction therapy is a well-established biomarker predicting treatment outcomes, while no genomic biomarkers are routinely applied in clinics. In this study, we used multiomic data from... -
Oral microbiome diversity and composition before and after chemotherapy treatment in pediatric oncology patients
CONCLUSIONS: These findings indicate that chemotherapy-induced microbiome shifts associate with OM risk, highlighting the potential for microbial markers to predict high-risk patients and support protective strategies. -
Ultra-low-input cell-free DNA sequencing for tumor detection and characterization in a real-world pediatric brain tumor cohort
Molecular profiling of pediatric central nervous system (CNS) tumors has important clinical utility for guiding diagnostic and therapeutic strategies. Cell-free DNA (cfDNA) from liquid biopsies has been used for minimally invasive tumor profiling and longitudinal disease assessment in adult oncology and pediatric hematology. However, in pediatric neuro-oncology, low cfDNA yields pose a major barrier to translating these assays from bench to bedside. Here, we implemented a low-coverage whole... -
Increased incidence of autoimmune haemolytic anaemia with paroxysmal cold haemoglobinuria features in paediatric cases in a changing viral environment post-COVID-19 pandemic
Paroxysmal cold haemoglobinuria (PCH) is a rare subtype of autoimmune haemolytic anaemia (AIHA) in children. It is characterised by complement-mediated intravascular haemolysis, triggered by biphasic Donath-Landsteiner (DL) antibodies that activate complement against the P antigen of red blood cells. We report four AIHA cases with PCH features, all presenting with haemoglobinuria following an upper respiratory tract infection (URTI). Direct antiglobulin tests confirmed complement fixation... -
Clustering of childhood acute leukemia in Finland: a nationwide register-based study
CONCLUSION: Overall, we found limited evidence for clustering. In the subgroup analyses, significant spatiotemporal clustering in acute lymphoblastic leukemia cases among children aged 1.5-5.99 years was observed, coinciding with the peak incidence in early childhood. Previous research has shown that this age group has distinct genetic characteristics and may possess a unique etiology. -
Risk of childhood brain tumors after exposure to CT radiation: A nationwide population-based case-control study in Finland
In this nationwide population-based case-control study, we assessed the risk of childhood brain tumors following exposure to radiation from CT. Brain tumors diagnosed in Finland during 1990-2016 were identified by the Finnish Cancer Registry. For each case, three age- and sex-matched controls were sampled from the Population Information System. The study population was linked to a CT dataset encompassing pediatric CTs performed in Finland during 1975-2011. We implemented a 5-year lag period and... -
SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells
Glucocorticoids are a mainstay in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). The glucocorticoid receptor (GR), a ligand-activated transcription factor (TF), mediates their actions. Chromatin occupancy, chromatin-protein networks (chromatomes) and gene programmes of GR are regulated by SUMOylation, a post-translational modification with therapeutic implications in other hematomalignancies. To unravel the GR-SUMOylation crosstalk in B-ALL, we induced hypoSUMOylation in NALM6... -
Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3-PBX1 fusion, is associated with intermediate risk and central nervous system (CNS) infiltration at relapse. Using our previously generated TCF3-PBX1 conditional knock-in mice, we established a model to study relapsed clones after in vivo chemotherapy treatment, CNS infiltration, and clonal dynamic evolution of phenotypic diversity at the single cell-level using next-generation...
2024
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Risk of childhood brain tumors after exposure to CT radiation: A nationwide population-based case-control study in Finland
In this nationwide population-based case-control study, we assessed the risk of childhood brain tumors following exposure to radiation from CT. Brain tumors diagnosed in Finland during 1990-2016 were identified by the Finnish Cancer Registry. For each case, three age- and sex-matched controls were sampled from the Population Information System. The study population was linked to a CT dataset encompassing pediatric CTs performed in Finland during 1975-2011. We implemented a 5-year lag period and... -
Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia
CONCLUSIONS: Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism. -
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. A part of the...
2023
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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 t(12;21)(p13;q22) translocation, leading to the ETV6::RUNX1 (E::R) 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. We... -
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. ALLIUM uses DNA methylation... -
Dual direction associations between common autoimmune diseases and leukemia among children and young adults: A systematic review
CONCLUSIONS: The results of this systematic review indicate that AI diseases in childhood are associated with a moderately increased risk of leukemia. The association for individual AI diseases needs further investigation. -
Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM
CONCLUSION: Patients with respective molecular alterations benefit from treatment with ALK, NTRK, and BRAF inhibitors as previously described. No survival benefit was observed with MTT for mutations in the MEK, CDK, other kinase, or mTOR signaling pathways. The noninterventional character of a registry has to be taken into account when interpreting these data and underlines the need for innovative interventional biomarker-driven clinical trials in pediatric oncology. -
Pre-harvest CD34<sup>+</sup> cell counts predicted peripheral blood stem cell collection yields
No abstract -
<em>In vivo</em> interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution
In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct... -
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... -
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...
2022
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Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing... -
Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood <em>KMT2A</em>-rearranged Acute Leukemia
Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-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 KMT2A-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... -
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. Almost all providers performed baseline coagulation studies, but only 59%... -
Incidence trends of childhood central nervous system tumors in Finland 1990-2017
CONCLUSIONS: Utilizing the high-quality and completeness of data in the Finnish Cancer registry, we found that the incidence of pediatric CNS tumors in Finland has increased slightly from 1990 until 2017. Although variations in diagnostic and registration practices over time might have affected the rates, the trend may also reflect a true increase in incidence. -
Successful eradication of chronic myeloid leukemia in a child despite allogeneic graft rejection
CONCLUSION: This case suggests that even a short antileukemic effect by an allogeneic transplant may succeed in eradicating CML. -
Trends in ferritin measurements in children and adolescents: A Finnish 9-year observational study
CONCLUSION: Ferritin measurement has increased greatly among children and adolescents. Our results suggest that public interest and popular trends can significantly influence health care practices. This calls for further investigation into the causes and consequences of such a phenomenon. Prospective randomised intervention studies are needed to evaluate the utility of iron supplementation in patients with low iron storage levels. -
No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy
CONCLUSION: In this retrospective analysis, only a subgroup of patients with good response at allo-HSCT survived. There was no survival benefit of allo-transplanted patients compared to matched controls, suggesting the absence of a clinically relevant graft-versus-RMA effect in the current setting. The results of this analysis do not support further implementation of allo-HSCT in RMA stage IV patients. -
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 PRMT7 mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of PRMT7 by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated... -
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... -
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. Incidence... -
Incidence and outcomes of cancer in 16- to 17-year-old adolescents
No abstract
2021
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Incidence and outcomes of cancer in 16- to 17-year-old adolescents
No abstract -
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 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received... -
Late adverse effects of childhood acute lymphoblastic leukemia treatment on developing dentition
CONCLUSIONS: Children and adolescents who received ALL treatment were at risk for dental damage. Young age and high-intensity therapy were associated with the severity of dental abnormalities. -
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. We investigated the expression of the BCL6 protein in a population-based cohort of paediatric B-ALL cases and detected moderate to strong... -
<em>IGF2BP3</em> 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 (IGF2BP3) belongs to a family of RNA-binding proteins involved in localization, stability, and translational regulation of target RNAs. IGF2BP3 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. We sought to identify... -
Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li-Fraumeni syndrome
No abstract
2020
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Trends of computed tomography use among children in Finland
CONCLUSIONS: The frequency of pediatric CTs in Finland started to decrease after 2002. Apart from chest and orthopedic CTs, the utilization of pediatric CT imaging declined in recent years, most likely explained by improved awareness of medical radiation risks and reliance on alternative modalities such as MRI and ultrasound. -
Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities
CONCLUSIONS: Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia. -
Immunogenomic Landscape of Hematological Malignancies
No abstract -
SIX6 is a TAL1-regulated transcription factor in T-ALL and associated with inferior outcome
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy driven by abnormal activity of transcription factors. Here we report an aberrant expression of the developmental transcription factor SIX6 in the TAL1-subtype of T-ALL. Our results demonstrate that the binding of TAL1 and GATA3 transcription factors into an upstream enhancer element directly regulates SIX6 expression. High expression of SIX6 was associated with inferior event-free survival within three independent patient... -
Randomized controlled and double-blinded study of Caphosol versus saline oral rinses in pediatric patients with cancer
CONCLUSIONS: No difference in prevention of oral mucositis was observed between the use of Caphosol or saline rinses. -
Signalling input from divergent pathways subverts B cell transformation
Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer¹. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert... -
Immunogenomic Landscape of Hematological Malignancies
Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and... -
Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis
CONCLUSIONS: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms. -
Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)
No abstract -
Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia
Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in B-ALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations... -
Predicting residential radon concentrations in Finland: Model development, validation, and application to childhood leukemia
Objectives Inhaled radon gas is a known alpha-emitting carcinogen linked especially to lung cancer. Studies on higher concentrations of indoor radon and childhood leukemia have conflicting but largely negative results. In this study, we aimed to create a sophisticated statistical model to predict indoor radon concentrations and apply it to a Finnish childhood leukemia case-control dataset. Methods Prediction was based on ~80 000 indoor radon measurements, which were linked to national registries... -
Characterization of immune response against Mycobacterium marinum infection in the main hematopoietic organ of adult zebrafish (Danio rerio)
Tuberculosis remains a major global health challenge. To gain information about genes important for defense against tuberculosis, we used a well-established tuberculosis model; Mycobacterium marinum infection in adult zebrafish. To characterize the immunological response to mycobacterial infection at 14 days post infection, we performed a whole-genome level transcriptome analysis using cells from kidney, the main hematopoietic organ of adult zebrafish. Among the upregulated genes, those... -
Nursing intensity scores did not correlate well with reimbursement claims for infant bronchiolitis
CONCLUSION: Hospital reimbursement claim for a PICU admission was three times as much as a ward admission and reimbursement claims for bronchiolitis did not match with nursing intensity scores.
2019
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Prediction of leukocyte counts during paediatric acute lymphoblastic leukaemia maintenance therapy
Maintenance chemotherapy with oral 6-mercaptopurine and methotrexate remains a cornerstone of modern therapy for acute lymphoblastic leukaemia. The dosage and intensity of therapy are based on surrogate markers such as peripheral blood leukocyte and neutrophil counts. Dosage based leukocyte count predictions could provide support for dosage decisions clinicians face trying to find and maintain an appropriate dosage for the individual patient. We present two Bayesian nonlinear state space models... -
Predicting residential radon concentrations in Finland: Model development, validation, and application to childhood leukemia
Objectives Inhaled radon gas is a known alpha-emitting carcinogen linked especially to lung cancer. Studies on higher concentrations of indoor radon and childhood leukemia have conflicting but largely negative results. In this study, we aimed to create a sophisticated statistical model to predict indoor radon concentrations and apply it to a Finnish childhood leukemia case-control dataset. Methods Prediction was based on ~80 000 indoor radon measurements, which were linked to national registries... -
Characterization of immune response against Mycobacterium marinum infection in the main hematopoietic organ of adult zebrafish (Danio rerio)
Tuberculosis remains a major global health challenge. To gain information about genes important for defense against tuberculosis, we used a well-established tuberculosis model; Mycobacterium marinum infection in adult zebrafish. To characterize the immunological response to mycobacterial infection at 14 days post infection, we performed a whole-genome level transcriptome analysis using cells from kidney, the main hematopoietic organ of adult zebrafish. Among the upregulated genes, those... -
Parental occupational exposure to low-frequency magnetic fields and risk of leukaemia in the offspring: findings from the Childhood Leukaemia International Consortium (CLIC)
CONCLUSIONS: In this large international dataset applying a comprehensive quantitative JEM, we did not find any associations between parental occupational ELF-MF exposure and childhood leukaemia. -
Data-driven characterization of molecular phenotypes across heterogeneous sample collections
Existing large gene expression data repositories hold enormous potential to elucidate disease mechanisms, characterize changes in cellular pathways, and to stratify patients based on molecular profiles. To achieve this goal, integrative resources and tools are needed that allow comparison of results across datasets and data types. We propose an intuitive approach for data-driven stratifications of molecular profiles and benchmark our methodology using the dimensionality reduction algorithm... -
Nursing intensity scores did not correlate well with reimbursement claims for infant bronchiolitis
CONCLUSION: Hospital reimbursement claim for a PICU admission was three times as much as a ward admission and reimbursement claims for bronchiolitis did not match with nursing intensity scores. -
Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies
Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and in... -
Insulin-dependent diabetes: A chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia
Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range: 1.7-9.2). We describe the clinical course of pancreatitis and... -
Acute Lymphoblastic Leukemia With INPP5D-ABL1 Fusion Responds to Imatinib Treatment
We describe a patient with Down syndrome whose precursor B-cell acute lymphoblastic leukemia cells expressed INPP5D-ABL1 fusion gene that resulted in a reciprocal chromosome translocation t(2;9)(q27;q34). The fusion gene was present as a small subclone in the primary disease but was first identified at relapse when the subclone had expanded into a major clone. At relapse, the patient responded poorly to conventional induction chemotherapy but a transient morphologic remission was achieved after...
2018
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Insulin-dependent diabetes: A chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia
Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range: 1.7-9.2). We describe the clinical course of pancreatitis and... -
Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)
The only well-established risk factors for childhood leukemia are high-dose ionizing radiation and Down syndrome. Computerized tomography is a common source of low-dose radiation. In this study, we examined the magnitude of the risk of childhood leukemia after pediatric computed tomography examinations. We evaluated the association of computed tomography scans with risk of childhood leukemia in a nationwide register-based case-control study. Cases (n=1,093) were identified from the... -
Effects of incomplete residential histories on studies of environmental exposure with application to childhood leukaemia and background radiation
When evaluating environmental exposures, residential exposures are often most relevant. In most countries, it is impossible to establish full residential histories. In recent publications, childhood leukaemia and background radiation have been studied with and without full residential histories. This paper investigates the consequences of lacking such full data. Data from a nationwide Finnish Case-Control study of Childhood Leukaemia and gamma rays were analysed. This included 1093 children... -
Erratum: Whole-exome sequencing identifies germline mutation in <em>TP53</em> and <em>ATRX</em> in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
No abstract -
Whole-exome sequencing identifies germline mutation in <em>TP53</em> and <em>ATRX</em> in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with... -
HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or... -
Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere...
2017
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Deregulation of the non-coding genome in leukemia
Methodological advances that allow deeper characterization of non-coding elements in the genome have started to reveal the full spectrum of deregulation in cancer. We generated an inducible cell model to track transcriptional changes after induction of a well-known leukemia-inducing fusion gene, ETV6-RUNX1. Our data revealed widespread transcriptional alterations outside coding elements in the genome. This adds to the growing list of various alterations in the non-coding genome in cancer and... -
Derailed regulatory network in childhood acute leukaemia
No abstract -
Overexpression of PTP4A3 in ETV6-RUNX1 acute lymphoblastic leukemia
Cell signalling, which is often derailed in cancer, is a network of multiple interconnected pathways with numerous feedback mechanisms. Dynamics of cell signalling is intimately regulated by addition and removal of phosphate groups by kinases and phosphatases. We examined expression of members of the PTP4A family of phosphatases across acute leukemias. While expression of PTP4A1 and PTP4A2 remained relatively unchanged across diseases, PTP4A3 showed marked overexpression in ETV6-RUNX1 and...
2016
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Overexpression of PTP4A3 in ETV6-RUNX1 acute lymphoblastic leukemia
Cell signalling, which is often derailed in cancer, is a network of multiple interconnected pathways with numerous feedback mechanisms. Dynamics of cell signalling is intimately regulated by addition and removal of phosphate groups by kinases and phosphatases. We examined expression of members of the PTP4A family of phosphatases across acute leukemias. While expression of PTP4A1 and PTP4A2 remained relatively unchanged across diseases, PTP4A3 showed marked overexpression in ETV6-RUNX1 and... -
Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia
Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1... -
Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots
Progression of malignancy to overt disease requires multiple genetic hits. Activation-induced deaminase (AID) can drive lymphomagenesis by generating off-target DNA breaks at loci that harbor highly active enhancers and display convergent transcription. The first active transcriptional profiles from acute lymphoblastic leukemia (ALL) patients acquired here reveal striking similarity at structural variation (SV) sites. Specific transcriptional features, namely convergent transcription and Pol2... -
Background radiation and childhood leukemia: A nationwide register-based case-control study
High doses of ionizing radiation are an established cause of childhood leukemia. However, substantial uncertainty remains about the effect of low doses of radiation, including background radiation and potential differences between genetic subgroups of leukemia have rarely been explored. We investigated the effect of the background gamma radiation on childhood leukemia using a nationwide register-based case-control study. For each of the 1,093 cases, three age- and gender matched controls were... -
Single-centre study reports a 84% five-year overall survival rate for paediatric solid tumours
CONCLUSION: The treatment results in our study are comparable with those previously published. A comprehensive local database allows for a timely follow-up of the characteristics and quality of treatment of childhood malignancies. -
Residential mobility and the risk of childhood leukemia
CONCLUSION: Our results do not indicate that higher residential mobility or moving to municipalities with more inhabitants is associated with risk of childhood leukemia. -
Audits show that specialist paediatric training programmes are sensitive to medical, staffing and economic changes
CONCLUSION: Since 2003, a marked improvement had taken place in the paediatric training provided by regional central hospitals, partly because of the increase in paediatric specialist resources. This study underlines the importance of repeat audits and the need for co-opera-tion between the university hospital and regional hospitals, including regular visits. -
Redox-dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function
Sin3A-associated protein 30-like (SAP30L) is one of the key proteins in a multi-subunit protein complex involved in transcriptional regulation via histone deacetylation. SAP30L, together with a highly homologous SAP30 as well as other SAP proteins (i.e., SAP25, SAP45, SAP130, and SAP180), is an essential component of the Sin3A corepressor complex, although its actual role has remained elusive. SAP30L is thought to function as an important stabilizing and bridging molecule in the complex and to...