Childhood B cell leukemia: Intercepting the paths to progression.

B-cell Acute Lymphoblastic Leukemia (B-ALL) is the most common pediatric cancer, arising most often in children aged 2-5 years. This distinctive age distribution hints at an association between B-ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B-ALL surpass 90% in high-income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution of B-ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B-ALL and explores how this knowledge can inform preventive strategies.

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions.

SUMMARY: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

Differences in MRI measurements of lateral recesses and foramina in degenerative lumbar segments in upright versus decubitus symptomatic patients.

OBJECTIVE: To evaluate differences in measurements of the lateral recesses and foramina in degenerative lumbar segments on MR images in symptomatic patients obtained with the patient standing versus lying down and to analyze the relationship between possible differences and patients' symptoms. MATERIAL AND METHODS: We studied 207 disc levels in 175 patients aged between 17 and 75 years (median: 47 years) with low back pain. All patients underwent MRI in the decubitus position with their legs extended, followed by MRI in the standing position. We calculated the difference in the measurements of the lateral recesses (in mm) and in the foramina (area in mm2 and smallest diameter in mm) obtained in the two positions. To eliminate the effects of possible errors in measurement, we selected cases in which the difference between the measurements obtained in the two positions was ≥10%; we used Student's t-tests for paired samples to analyze the entire group and subgroups of patients according to age, sex, grade of disc degeneration, and postural predominance of symptoms. RESULTS: Overall, the measurements of the spaces were lower when patients were standing. For the lateral recesses, we observed differences ≥10% in 68 (33%) right recesses and in 65 (31.5%) left recesses; when patients were standing, decreases were much more common than increases (26% vs. 7%, respectively, on the right side and 24% vs. 7.5%, respectively, on the left side; p < 0.005). For the foramina, decreases in both the area and in the smallest diameter were also more common than increases when patients were standing: on the right side, areas decreased in 23% and increased in 4%, and smallest diameters decreased in 20% and increased 6%; on the left side, areas decreased in 24% and increased in 4%, and smallest diameters decreased in 17% and increased in 8% (p < 0.005). Considering the group of patients in whom the postural predominance of symptoms was known, we found significant differences in patients whose symptoms occurred predominantly or exclusively when standing, but not in the small group of patients whose symptoms occurred predominantly while lying. We found no differences between sexes in the changes in measurements of the recesses or foramina with standing. The differences between the measurements obtained in different positions were significant in patients aged >40 years, but not in younger groups of patients. Differences in relation to the grade of disc degeneration were significant only in intermediate grades (groups 3-6 in the Griffith classification system). CONCLUSION: MRI obtained with patients standing can show decreases in the lateral recesses and foramina related to the predominance of symptoms while standing, especially in patients aged >40 years with Griffith disc degeneration grade 3-6, thus providing additional information in the study of patients who have low back pain when standing in whom the findings on conventional studies are inconclusive or discrepant with their symptoms. Further studies are necessary to help better define the value of upright MRI studies for degenerative lumbar disease.

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.

The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/- B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/-Myd88+/- mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/- mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.

Editorial: Special Issue "Stem Cell Biology and Cancer".

Cancer stem cells (CSCs) are now well-established as key players in tumor initiation, progression, and therapy resistance [...].

Cooperative action of separate interaction domains promotes high-affinity DNA binding of Arabidopsis thaliana ARF transcription factors.

The signaling molecule auxin coordinates many growth and development processes in plants, mainly through modulating gene expression. Transcriptional response is mediated by the family of auxin response factors (ARF). Monomers of this family recognize a DNA motif and can homodimerize through their DNA-binding domain (DBD), enabling cooperative binding to an inverted binding site. Most ARFs further contain a C-terminal PB1 domain that is capable of homotypic interactions and mediating interactions with Aux/IAA repressors. Given the dual role of the PB1 domain, and the ability of both DBD and PB1 domain to mediate dimerization, a key question is how these domains contribute to DNA-binding specificity and affinity. So far, ARF-ARF and ARF-DNA interactions have mostly been approached using qualitative methods that do not provide a quantitative and dynamic view on the binding equilibria. Here, we utilize a DNA binding assay based on single-molecule Förster resonance energy transfer (smFRET) to study the affinity and kinetics of the interaction of several Arabidopsis thaliana ARFs with an IR7 auxin-responsive element (AuxRE). We show that both DBD and PB1 domains of AtARF2 contribute toward DNA binding, and we identify ARF dimer stability as a key parameter in defining binding affinity and kinetics across AtARFs. Lastly, we derived an analytical solution for a four-state cyclic model that explains both the kinetics and the affinity of the interaction between AtARF2 and IR7. Our work demonstrates that the affinity of ARFs toward composite DNA response elements is defined by dimerization equilibrium, identifying this as a key element in ARF-mediated transcriptional activity.

Childhood B-Cell Preleukemia Mouse Modeling.

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.

Revisiting the concept of childhood preleukemia.

Preleukemic has been used to describe children with a propensity to develop B cell acute lymphoblastic leukemia (B-ALL). However, leukemia-predisposing mutations can also be present in differentiated cells unable to transform. We postulate that preleukemia should only be used when such mutations arise in progenitors capable of evolving to B-ALL.

Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice.

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development. SIGNIFICANCE: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.

Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma.

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.

The Impact of Absorptive Capacity on Innovation: The Mediating Role of Organizational Learning.

Although the relevant literature has already demonstrated the impact that absorptive capacity has on companies' innovation capacity, we have found few studies that analyze the role of learning capability in this relationship. The main objective of this study was to examine the role of organizational learning in this relationship. For this purpose, a quantitative research approach was used. A total of 306 valid questionnaires were obtained from small and medium-sized Spanish companies in different sectors. The collected data were analyzed using the multivariate Partial Least Square (PLS) quantitative structural equation technique. According to the result, absorption capacity turns into innovation mainly when learning capacity is involved in this process. This study provides empirical evidence of this relationship and fills this gap. It can also help organizations understand and clarify what would be the most appropriate way in to manage knowledge to improve their innovation levels.

A Multidimensional Study of Absorptive Capacity and Innovation Capacity and Their Impact on Business Performance.

The aim of this paper is to understand how absorptive capacity and innovativeness influence business performance. Most previous studies have not considered the different dimensions of absorptive capacity and innovativeness. As a consequence, they have not analyzed the relationships between these dimensions, such as potential and realized absorptive capacity (RACAP) and product and process innovation. In our study, we analyzed the relationships between each of these dimensions and their effect on organizational performance. To achieve this, in addition to the theoretical foundation provided by the working hypotheses, a questionnaire was sent to 800 CEOs of Spanish companies in different sectors, obtaining a response rate of 38.25%. Structural equation modeling was applied to test the hypotheses. This study confirms the positive effect of absorptive capacity on innovation capacity, which in turn has a positive effect on business performance. Moreover, different dimensions of absorptive capacity and innovativeness play an important role in these relationships. This study contributes to a better understanding of how potential and RACAP influence the innovativeness of firms, both in their ability to innovate products and to improve business processes. In addition, it explores how these different innovations impact business performance and provide firms with knowledge on how to invest resources to increase profits. Future research should further study the inner workings of each of the dimensions analyzed to determine the importance of each dimension for business performance.

The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.

An immune window of opportunity to prevent childhood B cell leukemia.

The prevalence of childhood B cell acute lymphoblastic leukemia (B-ALL) is increasing, particularly in developed countries. There is no clear explanation for this increment, but recent data suggest that, besides genetic predisposition, stress in the immune system (e.g., an infection) might have an important role in B-ALL leukemogenesis. Here, we speculate on how this knowledge might impact B-ALL prevention strategies.

Differences in MRI measurements of lateral recesses and foramina in degenerative lumbar segments in upright versus decubitus symptomatic patients. / Cambios en recesos laterales y forámenes en segmentos degenerativos lumbares de pacientes sintomáticos estudiados mediante resonancia magnética en decúbito y bipedestación.

OBJECTIVE: To evaluate differences in measurements of the lateral recesses and foramina in degenerative lumbar segments on MR images in symptomatic patients obtained with the patient standing versus lying down and to analyze the relationship between possible differences and patients' symptoms. MATERIAL AND METHODS: We studied 207 disc levels in 175 patients aged between 17 and 75 years (median: 47 years) with low back pain. All patients underwent MRI in the decubitus position with their legs extended, followed by MRI in the standing position. We calculated the difference in the measurements of the lateral recesses (in mm) and in the foramina (area in mm2 and smallest diameter in mm) obtained in the two positions. To eliminate the effects of possible errors in measurement, we selected cases in which the difference between the measurements obtained in the two positions was ≥10%; we used Student's t-tests for paired samples to analyze the entire group and subgroups of patients according to age, sex, grade of disc degeneration, and postural predominance of symptoms. RESULTS: Overall, the measurements of the spaces were lower when patients were standing. For the lateral recesses, we observed differences ≥10% in 68 (33%) right recesses and in 65 (31.5%) left recesses; when patients were standing, decreases were much more common than increases (26% vs. 7%, respectively, on the right side and 24% vs. 7.5%, respectively, on the left side; p<0.005). For the foramina, decreases in both the area and in the smallest diameter were also more common than increases when patients were standing: on the right side, areas decreased in 23% and increased in 4%, and smallest diameters decreased in 20% and increased 6%; on the left side, areas decreased in 24% and increased in 4%, and smallest diameters decreased in 17% and increased in 8% (p<0.005). Considering the group of patients in whom the postural predominance of symptoms was known, we found significant differences in patients whose symptoms occurred predominantly or exclusively when standing, but not in the small group of patients whose symptoms occurred predominantly while lying. We found no differences between sexes in the changes in measurements of the recesses or foramina with standing. The differences between the measurements obtained in different positions were significant in patients aged>40 years, but not in younger groups of patients. Differences in relation to the grade of disc degeneration were significant only in intermediate grades (groups 3-6 in the Griffith classification system). CONCLUSION: MRI obtained with patients standing can show decreases in the lateral recesses and foramina related to the predominance of symptoms while standing, especially in patients aged>40 years with Griffith disc degeneration grade 3 to 6, thus providing additional information in the study of patients who have low back pain when standing in whom the findings on conventional studies are inconclusive or discrepant with their symptoms. Further studies are necessary to help better define the value of upright MRI studies for degenerative lumbar disease.

Infectious triggers and novel therapeutic opportunities in childhood B cell leukaemia.

B cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer. Although treatment has advanced remarkably in the past 50 years, it still fails in ~20% of patients. Recent studies revealed that more than 5% of healthy newborns carry preleukaemic clones that originate in utero, but only a small percentage of these carriers will progress to overt B-ALL. The drivers of progression are unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. Emerging evidence shows that a major driver for the conversion from the preleukaemic state to the B-ALL state is exposure to immune stressors, such as infection. Here, we discuss our current understanding of the environmental triggers and genetic predispositions that may lead to B-ALL, highlighting lessons from epidemiology, the clinic and animal models, and identifying priority areas for future research.