As one of the leading internet information platforms (EMF-Portal at RWTH Aachen University www.emf- portal.org) we systematically screen and summarize VFLHQWLÀFUHVHDUFKRQWKHHIIHFWVRIHOHFWURPDJQHWLFÀHOGV (EMF). Thus we came across the publications by Tabrizi and Bidgoli (2015) and Tabrizi and Hosseini (2015) on prenatal and postnatal exposure to high voltage power lines and the risk of childhoodacutelymphoblasticleukemia (ALL), both published in your journal in April and December 2015, respectively.
Tabrizi MM, Bidgoli SA (2015). Increased risk of childhoodacutelymphoblasticleukemia (ALL) by prenatal and postnatal exposure to high voltage power lines : a case control study in Isfahan, Iran. Asian Pac J Cancer Prev, 16, 2347-50.
Figure 1. Unsupervised hierarchical clustering of gene expression data from bone marrow samples of 31 children with acutelymphoblasticleukemia. Cluster dendrogram based on 333 fil- tered probe sets (see methods for filter criteria). The upper main branch includes precursor B cell leukemias, whereas the lowest branch identifies two T-cell leukemias. The left column shows the patient number, cytogenetic characterization is listed in the middle column, risk group assignment is pre- sented in the right column. The dendro- gram did not change substantially when more (or even all) probe sets were used (results not shown). *normal indicates DNA index of 1 and no TEL-AML1, BCR- ABL, E2A-PBX1 or MLL-AF4 rearrange- ment.
Intensification of chemotherapy for childhoodacutelymphoblasticleukemia (ALL) has generated 5-year sur- vival rates greater than 90%, but has been associated with an increase in therapy-related toxicity. 1 Asparaginase is a key drug in the treatment of childhood ALL and there is growing interest in its use as an anti-metastatic agent in breast cancer. 2 Asparaginase depletes the body of the non- essential amino acid asparagine through deamidation of asparagine into aspartic acid and ammonia, 3 and targets protein synthesis in malignant lymphoblasts by impairing the ability to synthesize asparagine. 4,5 Pancreatitis associ- ated with asparaginase therapy (AAP) is a frequent toxici- ty affecting 4−10% of children treated on contemporary ALL protocols, and is associated with severe complica- tions. 6–9 In addition, re-exposure to asparaginase after AAP is associated with a high risk (~50%) of a second episode of AAP, and thus AAP often entails truncation of asparag- inase therapy, thereby decreasing the patients’ chance of survival. 4,5,9 The mechanism(s) by which asparaginase causes pancreatitis are elusive, thus hampering attempts to identify patients with an altered risk of AAP. 10 The Ponte di Legno toxicity working group, therefore, initiated a study with three main purposes: (i) to define diagnostic consensus criteria for AAP; 11 (ii) to describe the phenotype of AAP in patients across multiple ALL trial groups; 9 and (iii) to explore genotype-phenotype associations, using a genome-wide approach, to identify patients with altered risk of AAP. 9,11 Genome-wide association (GWA) studies are agnostic by design, reporting phenotype-genotype associations without prior hypotheses and often including speculative mechanisms. Replication of GWA study results are thus a requisite for credibility Accordingly, this study presents results from the largest AAP GWA study so far, with a strong focus on investigating previously validat- ed variants associated with non-asparaginase-induced pancreatitis and replicating top results in similar childhood ALL cohorts.
childhoodacutelymphoblasticleukemia. We prospectively com- pared the efficacy and safety of antithrombotic interventions in the consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acutelymphoblasticleukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low molecular weight heparin (enoxaparin) or activity-adapt- ed antithrombin throughout induction therapy. The primary objective of the study was to determine whether enoxaparin or antithrombin reduces the incidence of thromboembolism as compared to unfractionated heparin. The principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of throm- boembolism (8.0%) compared with those randomized to enoxaparin (3.5%; P=0.011) or antithrombin (1.9%; P<0.001). The proportion of patients who refused antithrombotic treatment as allocated was 3% in the unfractionated heparin or antithrombin arms, and 33% in the enoxaparin arm. Major hemorrhage occurred in eight patients (no differences between the groups). The 5-year event-free survival was 80.9±2.2% among patients THROMBOTECT – a randomized study
LCH is a rare, clinically heterogeneous neoplasm of immature dendritic cells (its manifestations range from isolated bone lesions to systemic disease with involvement of two or more visceral organs) that is most frequent in children (Jaffe et al., 2001). Development of LCH following T- ALL is extremely rare. Few brief reports have stated a relationship between LCH and systemic Juvenile Xantogranuloma (JXG) following T-ALL (Rodig et al., 2007; Perez-Becker et al., 2010). It is suggested that LCH/JXG are clonally related to T-ALL and present persistent expression of constitutively active NOTCH1. Perez-Becker et al. reported the case of a 5-year- old female that developed an aggressive JXG only 5 months after the diagnosis of T-cell acutelymphoblasticleukemia. They reported identical bi-allelic T-cell receptor-γ (TCR-γ) rearrangement in both neoplasms. Rodig and coworkers describe the case of a 3;7 year old patient who eighteen months after initial diagnosis developed an aggressive Langerhans cell Histiocytosis. Both neoplasms harbored not only the same (TCR-γ) rearrangement, but also identical, synergistic activating NOTCH1 mutations, affecting exons 27 and 34. Moreover, the analysis of 24 cases of LCH and Rosai-Dorfman disease in patients without prior history of T- ALL revealed no mutations. These reports highlight the unique nature of the mutations found in this work, emphasizing its exceptional character.
20 µg of whole protein lysate from ALL patient samples were used to perform quantitative western blot analysis as described in Figure 14. A) The PTK candidate, BTK, was selected as a representative WB for the selected 18 PTK. The serially diluted recombinant protein was loaded in the first four lanes and the total amount (in µg) is specified. Only green bands that coincided with the molecular weight of the recombinant protein were considered as the target protein. β-actin was used as a loading control (red bands). B) A heat map of the indicated PTK was generated. The analyzed PTK and the ALL patient ID are indicated in the y- and x-axis, respectively. The ALL immunophenotype of the samples is depicted. Highly expressed PTK are shown in shades of yellow, and non-expressed PTK are shown in black, according to the color scale. C) Unsupervised cluster analysis (Pearson correlation) groups patients with related expression profiles. Mature CD3 and CD19 cells isolated from buffy coats were included in the analysis. c-ALL= common ALL; ETV6-RUNX1= ALL with ETV6-RUNX1 rearrangement; ALL= acutelymphoblasticleukemia.
The abnormal chromosomal number in ALL defines distinct subtypes with different response to treatment. High hyperdiploid is a subtype defined based on cytogenetic nomenclature as chromosomal count between 47 and 57; the definition criteria are universally accepted. High hyperdiploid is one of the common childhood malignancies comprising 30% of all pediatric B cell–precursor ALL. Molecularly, high hyperdiploid ALL is characterized by massive aneuploidy (abnormal number of chromosomes), authenticating a nonrandom gain of chromosomes. For example, some or all of +X, +4, +6, +10, +14, +17, +18, and +21 and other trisomies have been reported. However, the pathogenetic phenomenon of chromosomal gains remains poorly understood, but it generally is believed that gene dosage effects are of significance (Chilton et al., 2014). Genetic abnormalities like driver fusion gene is not observed in the vast majority of high hyperdiploid ALL cases. However, there is a possibility that there is yet unidentified primary aberrations present due to the low resolution of most genetic screening techniques. Previously such concealed events have been reported in aneuploid tumors, for example, the identification of structural dysregulation resulting in rearrangements of cytokine receptor-like factor 2 (CRLF2) in a large number of ALL patients with Down syndrome and microdeletions leading to the transmembrane protease, serin 2 (TMPRSS2)/v-its erythroblastosis virus E26 oncogene homolog (ERG) hybrid gene in prostate cancer (Mullighan et al., 2009). Profiling of a fusion gene in high hyperdiploid ALL would be of prima facie clinical importance, which may perhaps simplify the diagnostic procedures and hence provide novel treatment options. Clinical features of high hyperdiploid ALL was associated with a relatively low WBC count and a B-cell precursor immunophenotype. The prognosis of five-year overall survival rates (OS) is close to 90%.
higher in the group treated with E. coli asparaginase than in that treated with ERW-asparag- inase. Similar results were found in a study by Woo et al. 8 A different trend has been found in studies performed so far in patients treated with PEG-asparaginase. Vieira Pinheiro et al. 30 studied patients treated with PEG-asparag- inase within the German Cooperative AcuteLymphoblasticLeukemia (COALL) study and Rizzari et al. 15 patients treated with the same product within the AIEOP ALL 2000 study. Overall, both studies showed that CSF asparagine levels in patients treated with PEG- asparaginase were undetectable (i.e., below the detection limit) only in a fraction of patients, no matter if serum asparaginase activity levels were much higher than 100 IU/L. Additional studies reported by the Nordic Society of Pediatric Hematology and Oncology and even more recently by the Dutch ChildhoodLeukemia Study Group (DCLSG) confirmed these observations. 14,27,31,32
With 80 % of all leukemic cancers, especially the acutelymphoblasticleukemia (ALL) is the most common leukemia in childhood and also the most frequent cancer in children and adolescents with the second highest number of cancer related deaths (Pui, Evans 1998; Siegel et al. 2016). Improvements of treatment regimen, supportive care and risk stratification increased cure rates of pediatric ALL over the past decades to more than 80 % (American Cancer Society 2016 a; Hunger et al. 2012; Moricke et al. 2010; Siegel et al. 2016). However, many patients encounter relapse of their disease which is associated with a poor outcome (Henze et al. 1991; Irving 2016; Malempati et al. 2007), even when risk stratification according to minimal residual disease (MRD) was assessed before ( Conter et al. 2010; Schrappe et al. 2000; van Dongen et al. 1998). These patients are hard to treat because cells of relapsed leukemia cases evolved an intrinsic chemoresistance, which is not present when compared to the corresponding original diagnosed leukemia (Klumper et al. 1995; Pogorzala et al. 2015). Therefore, it is necessary to develop new approaches which allow identification of high risk patients in order to improve their therapy leading to increased patient outcome and survival.
An estimate of 6000 US citizens develop acutelymphoblasticleukemia (ALL) every year (Siegel et al, 2012). In 80% of these cases the leukemia cells express B lymphocyte markers alongside early progenitor antigens (Armstrong, 2005), consistent with the malignant transformation of conventional precursor B lymphocytes during their maturation in the bone marrow (Zhou et al, 2012). Over the last 50 years, the introduction of combination chemotherapy, improved risk stratification and enhanced supportive care led to a steady increase in the survival rates of ALL patients. Today, state of the art therapy cures an average of 85% of childhood and 40% of adult ALL cases (Pui et al, 2009; Hunger et al, 2012; Sive et al, 2012). However, ALL treatment remains challenging. The extensive exposure of children to cytotoxic agents causes side effects including cognitive impairment and second malignancies even years after completing therapy (Conklin et al, 2012; Mody et al, 2008; Nottage et al, 2011). Moreover, despite strong efforts 60% of adults still succumb to their disease. It is widely accepted that further improvements of ALL therapy will have to rely on novel more targeted treatment approaches. This includes the specific inhibition of kinases that promote the clonal expansion of B-ALL cells, using small molecule kinase inhibitors. However, the successful application of such targeted agents requires a profound knowledge of the biological mechanisms driving malignant proliferation.
Beyond low bone mineral content and fractures many other factors may account for impaired bone health in patients with ALL, such as alterations in bone metabolism, chronic bone pain and stunted growth ( 17 – 20 ). In addition, the hormone vitamin D plays an important role in the maintenance of calcium homeostasis and thereby bone health in childhood and adolescence ( 21 ). Given its additional functions such as regulation immunity and cellular differentiation, an optimal vitamin D status may be important especially for patients with cancer ( 22 ). Therefore, the assessment of bone health in a population at risk for bone disease should account for all of the above. This is a difficult and complex task, in particular since the assessment of bone metabolism depends on age- and pubertal stage-appropriate interpretation of biochemical surrogate parameters.
Support for the hypothesis that the early-life immune environment is a modifier of pediatric B cell precursor (BCP) acutelymphoblasticleukemia (ALL) progression comes from a variety sources. A large body of epidemiologic data implicates infection in the disease etiology; protective effects have been reported when surrogates of infection exposure, such as day are attendance, are analyzed, but apparently contradictory findings have emerged from studies of documented early infections. In addition, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, and levels of IL-10 in neonatal blood spots have been correlated with ALL progression. The discovery that ALL-initiating genetic events often occur in utero indicated a potential cell target for the immune influence and pro--‐ leukemic activity has been induced in ETV6-RUNX1-expressing BCP cells by immune signaling. Here, I will describe our studies using the Eµ-ret and E2A-PBX1 mouse models of BCP ALL to further
Results: The analyzed family showed a strong cancer history, presenting a 13-year-old boy with T-cell acutelymphoblasticleukemia, its father who died due to breast cancer at the age of 41, as well as a grand-father with lung cancer. Due to the different cancer types present within the family, the dysregulation of a ubiquitously expressed gene seemed likely. Utilizing Trio-calling based on WES we identified a rare heterozygous germline mutation P298S (rs148308569, MAF<0.01) in the double- strand break repair protein RAD21. RAD21 is a member of the cohesin complex, which not only controls post-replicative DNA-repair, but is essential for proper chromosome segregation and the prevention of inappropriate recombination between repetitive regions. The presence of the mutation could be verified in both germline and tumor sample of the patient as well as its father, while the variant was absent in the healthy mother. RAD21 P298S is located in the interaction domain of RAD21 with two additional cohesion complex genes (WAPL and PDS5B) and therefore likely to disturb protein-protein-binding relevant for proper chromosome segregation. In addition, disturbed DNA-repair after radiation induced double-strand-breaks mediated through RAD21 P298S is supported by the patient’s treatment
AML is a heterogenous, clonal disease propagated by leukemia initiating cells with stem cell like characteristics. As a result, AML is described as a “stem cell disease”. Furthermore, recent studies have shown that high expression of stem cell genes in AML patients is strongly associated with disease progression and poor clinical parameters (Eppert et al., 2011; Gentles et al., 2010; Ng et al., 2016). Our analyses indicate that TET3 is a stem cell associated gene, higher expressed in murine HSCs and in human HSPCs compared to mature hematopoietic subpopulations (Figure 12D and Figure 13A). Moreover, Tet3 is the highest expressed Tet gene in both long-term as well as short-term murine HSCs (Figure 12C). Notably, in human AML patients we observe that TET3 is aberrantly higher expressed in the majority of de novo AML patients compared to the healthy stem progenitors, independent of the mutational characteristics of the patients (Figure 14A and 14C). The Cancer Genome Atlas Research Network using DNA and RNA sequencing has analyzed 200 clinically annotated adult cases of de novo AML. This data set also shows a broad range of TET3 expression in patients, among which are a large sub- category of patients that exhibit high TET3 expression.
First, the median and standard deviation of actual ANC measurements are very accu- rately matched by the simulation using the estimated parameters (compare the first two entries in the middle boxplot of figure 7.31). Concerning the patientwise observed and simulated minimal and maximal ANC values, the model demonstrates a correspond- ing weakened chemotherapy-induced myelosuppression, respectively overproduction of ANCs compared to the high measured variability. This variability is biologically and clinically very plausible due to the aforementioned external events and uncertain- ties, although periods of severe infections were already excluded. The reproducibility of the median and avoidance of over-fitting of the extreme values are in our opinion good properties of a mathematical model. Given this good correspondence between cross-validated data and simulations, we feel encouraged to compare simulations of different treatment protocols as specified in table 7.19. Note, however, that general- izations of mathematical models personalized for data from one protocol to another have to be considered with extreme care (compare the discussion for acute myeloid leukemia models by ). Further, we want to highlight that the current model is not intended to describe the ANC extrema such that the results of the simulation study have to be treated with caution. The results shall serve as a preliminary assessment of the dose-effect relationship which has to be confirmed in future studies. The relationship might be stronger compared to the current model predictions and demonstrated by the clinical data in figure 7.32. The impact of model variations on the outcome of simulation studies is usually significant. We have tested the value of fixing the k tr parameter to
B lock of myeloid differentiation is one of the hallmarks of acute myeloid leukaemia (AML). First insights into this key mechanism were gained by the discovery of the t(8;21)(q22;q22) translocation, which was the ﬁrst balanced translocation described in a tumour and results in the RUNX1/ RUNX1T1 fusion gene (also known as AML1/ETO) 1,2 . The RUNX1/RUNX1T1 rearrangement is one of the most frequent chromosomal aberrations in AML and deﬁnes an important clinical entity with favourable prognosis according to the World Health Organization classiﬁcation 3 . The RUNX1/RUNX1T1 fusion protein disrupts the core-binding factor complex, and thereby blocks myeloid differentiation. However, in vivo models indicate the requirement of additional lesions, such as of KIT or FLT3 mutations, for leukaemogenesis as the RUNX1/RUNX1T1 fusion gene alone is not sufﬁcient to induce leukaemia 4–8 . In the present study, we set out to identify additional mutations in AML t(8;21) and discovered frequent mutations of ZBTB7A—encoding a transcription factor important for the regulation of haematopoietic development 9 and tumour metabolism 10 . It is very likely that ZBTB7A mutations are one of the important missing links in RUNX1/RUNX1T1-driven leukaemogenesis.
biology, the sensitivity, efficacy and accuracy of both reactions depend on a complex combination of several factors including but not limited to, enzyme properties, buffer composition, primer sequences and reaction volume (Bagnoli et al., 2018; Hashimshony et al., 2016; Kalle et al., 2014; Picelli et al., 2013). Hence, optimizing these reactions requires substantial work, time and cost efforts (Bagnoli et al., 2018; Hagemann-Jensen et al., 2020). Therefore, some methods replace this typical pattern of reverse transcription and PCR amplification with linear amplifications using in vitro transcription. Although being supposedly less biased than PCR, this setup requires a second reverse transcription step (Hashimshony et al., 2016; Jaitin et al., 2014). In addition, PCR introduced biases and noise can be efficiently removed by integrating a molecular barcode or unique molecular identifier (UMI) already at the stage of cDNA conversion, enabling the removal of PCR duplicates computationally (Kivioja et al., 2012; Parekh et al., 2016). However, UMI integration is either performed at the 5` or 3` end of fragments, which precludes obtaining reads over the full gene body as one of the ends is enriched. Although all published scRNA-seq protocols require at least one reverse transcription step, several approaches are also possible in this reaction. Most methods use mRNA targeting oligo-dt primers in combination with reverse transcriptases derived from the moloney murine leukemia virus (MMLV), which are capable of performing template switching at the end of the RNA molecule and thereby introducing a second universal PCR handle using a template switching oligo (Zajac et al., 2013). Interestingly, the exact mechanism of this function was poorly understood until very recently (Wulf et al., 2019).
*t(15;17)/PML-RARA is treated separately from other AMLs. †In particular in patients with Down Syndrome and infants with acute megakaryoblastic leukemia, analysis of GATA1s mutations should be included. Identification of GATA1s- associated leukemia in trisomy 21 mosaicism can prevent overtreatment. ‡Includes all AMLs with normal karyotype, except for those included in the favorable subgroup; most of these cases are associated with poor prognosis, but they should be reported separately as they may respond differently to treatment. §For most abnormalities, adequate numbers have not been studied to draw firm conclusions on their prognostic significance. ∥Excluding recurrent genetic aberrations, as defined in the WHO 2008 classification. ¶Results in t(10;11)(p12;q23) are heterogeneous; therefore, intermediate prognosis may also be adequate. #Three or more chromosome abnormalities in the absence of one of the WHO-designated recurring translocations or inversions. **There are differences in the risk allocation of FLT3-ITD considering the allelic ratio. ††t(9;22) is rare, but it is included because its poor prognostic impact is known. Adapted from Creutzig et al. (Creutzig et al. 2012).