Search

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

Background: Subsequent short-latency leukemias are well-described among survivors of childhood cancer. However, late (5-14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort., Methods: Subsequent leukemias, among 25,656 five-year survivors, were self-reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures., Results: Seventy-seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0-14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9-42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%-0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0-12.1) and VLL (SIR 5.9, 95% CI 3.9-8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m 2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0-9.9)., Conclusions: In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Opinion Statement: Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The relative biological effectiveness (RBE) of densely ionizing radiation can depend on the biological context. From a radiological perspective, age is an important factor affecting health risks of radiation exposure, but little is known about the modifying impact of age on the effects of densely ionizing radiation. Herein, we addressed the influence of age on leukemogenesis induced by accelerator-generated fast neutrons (mean energy, ∼2 MeV). Male C3H/HeNrs mice were exposed to 137Cs γ rays (0.2-3.0 Gy) or neutrons (0.0485-0.97 Gy, γ ray contamination 0.0105-0.21 Gy) at 1, 3, 8, or 35 weeks of age and observed over their lifetimes under specific pathogen-free conditions. Leukemia and lymphoma were diagnosed pathologically. Hazard ratio (HR) and RBE for myeloid leukemia mortality as well as the age dependence of these two parameters were modeled and analyzed using Cox regression. Neutron exposure increased HR concordant with a linear dose response. The increase of HR per dose depended on age at exposure, with no significant dose dependence at age 1 or 3 weeks but a significant increase in HR of 5.5 per Gy (γ rays) and 16 per Gy (neutrons) at 8 weeks and 5.8 per Gy (γ rays) and 9 per Gy (neutrons) at 35 weeks. The RBE of neutrons was 2.1 (95% confidence interval, 1.1-3.7), with no dependence on age. The development of lymphoid neoplasms was not related to radiation exposure. The observed increasing trend of radiation-associated mortality of myeloid leukemia with age at exposure supports previous epidemiological and experimental findings. The results also suggest that exposure at the susceptible age of 8 or 35 weeks does not significantly influence the RBE value for neutrons for induction of leukemia, unlike what has been documented for breast and brain tumors., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objectives: This study aimed to perform a systematic review and meta-analysis to investigate the relationship between wood dust exposure and leukemia. The objectives included synthesizing available evidence, assessing its quality, identifying potential sources of heterogeneity, and drawing conclusions regarding the association between wood dust and leukemia., Methods: A systematic literature search was conducted to identify studies meeting that report on the association between wood dust and leukemia. The Joanna Briggs Institute Critical Appraisal tools were employed to ensure robust quality assessment. Meta-analysis, using random-effects models, synthesized evidence from studies with low risk of bias. Overall odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses explored potential sources of heterogeneity., Results: The meta-analysis included a comprehensive review of various study types, encompassing 7 studies that examined the association between wood dust exposure and leukemia risk. The analysis revealed a statistically significant positive association, with an overall odds ratio (OR) of 1.56 (95% CI: 1.15-2.12). This indicates that individuals exposed to wood dust are 1.56 times more likely to develop leukemia compared to those not exposed, with the 95% confidence interval ranging from 1.15 to 2.12, highlighting a substantial risk elevation across different study designs. Quality assessment using The Joanna Briggs Institute Critical Appraisal tools demonstrated a low risk of bias across all included studies, enhancing the credibility of the observed association. Subgroup analyses were conducted to explore potential sources of heterogeneity within the studies. Notably, subgroup analysis based on the year of the study revealed significant differences, as indicated by an I^2 value of 87%. The robustness of these results underscores the importance of addressing wood dust exposure as an occupational hazard, particularly in industries related to woodworking and forestry., Conclusion: This meta-analysis provides robust evidence supporting an increased risk of leukemia associated with wood dust exposure implying proactive measures in people exposed to dust., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Soleimani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Embryonic and fetal hematopoietic stem and progenitor cells differ in some key properties from cells that are part of the adult hematopoietic system. These include higher proliferation and self-renewal capacity, different globin gene usage, and differing lineage biases. Although these evolved to cover specific requirements of embryonic development, they can have serious consequences for the pathogenesis of hematologic malignancies that initiate prebirth in fetal blood cells and may result in a particularly aggressive disease that does not respond well to treatments that have been designed for adult leukemias. This indicates that these infant/pediatric leukemias should be considered developmental diseases, where a thorough understanding of their unique biology is essential for designing more effective therapies. In this review, we will highlight some of these unique fetal properties and detail the underlying molecular drivers of these phenotypes. We specifically focus on those that are pertinent to disease pathogenesis and that may therefore reveal disease vulnerabilities. We have also included an extensive description of the origins, phenotypes, and key molecular drivers of the main infant and pediatric leukemias that have a known prenatal origin. Importantly, successes in recent years in generating faithful models of these malignancies in which cellular origins, key drivers, and potential vulnerabilities can be investigated have resulted in uncovering potential, new therapeutic avenues., Competing Interests: Conflict of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to air pollution has been proposed as one of the potential risk factors for leukaemia. Work-related formaldehyde exposure is suspected to cause leukaemia., Methods: We conducted a nested register-based case-control study on leukaemia incidence in the Viadana district, an industrial area for particleboard production in Northern Italy. We recruited 115 cases and 496 controls, frequency-matched by age, between 1999 and 2014. We assigned estimated exposures to particulate matter (PM 10 , PM 2.5 ), nitrogen dioxide (NO 2 ), and formaldehyde at residential addresses, averaged over the susceptibility window 3rd to 10th year prior to the index date. We considered potential confounding by sex, age, nationality, socio-economic status, occupational exposures to benzene and formaldehyde, and prior cancer diagnoses., Results: There was no association of exposures to PM 10 , PM 2.5 , and NO 2 with leukaemia incidence. However, an indication of increased risk emerged for formaldehyde, despite wide statistical uncertainty (OR 1.46, 95%CI 0.65-3.25 per IQR-difference of 1.2 μg/m 3 ). Estimated associations for formaldehyde were higher for acute (OR 2.07, 95%CI 0.70-6.12) and myeloid subtypes (OR 1.79, 95%CI 0.64-5.01), and in the 4-km buffer around the industrial facilities (OR 2.78, 95%CI 0.48-16.13), although they remained uncertain., Conclusions: This was the first study investigating the link between ambient formaldehyde exposure and leukaemia incidence in the general population. The evidence presented suggests an association, although it remains inconclusive, and a potential significance of emissions related to industrial activities in the district. Further research is warranted in larger populations incorporating data on other potential risk factors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alessandro Marcon reports financial support was provided by ATS della Val Padana. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Leukemia is associated with exposure to radiation, benzene derivatives, and pesticides. Previous research has documented an increase in work-related leukemia in the Latin American Andean region. To date, there are only few studies in Ecuador on the impact of oil exploitation on adjacent indigenous communities. Our study aims to show the impact of leukemia on the working-age population. For the calculation of morbidity and mortality rates, we used hospital discharge and death records from the National Institute of Statistics of Ecuador. These data were collected and adjusted to the corresponding province's population for further analysis. Large differences were observed between provinces in adjusted rates of leukemia mortality and morbidity in the working-age population. The variations in altitude among different areas in Ecuador give the provinces a distinct geographic identity. Likewise, the provinces with the highest morbidity and mortality rankings, such as Azuay, Loja, Imbabura, and Tungurahua, have an average altitude above 2000 meters. As a result, there are variations in the average temperature, exposure to solar and cosmic radiation, and mining and farming methods. The observed differences warrant the future collection of geolocation data for affected individuals. This could help to better understand how leukemia cases have demogrpahic hotspots in the country, identify possible risk factors associated with the disease in each region, and design more effective prevention and control strategies., Competing Interests: The authors declare no competing interests with this work., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML. [ABSTRACT FROM AUTHOR]

In the article, the authors present the results of their study on the incidence of leukemia in children living near nuclear power plants (NPP) in Germany in 2004 to 2019 to analyze the relationship of residential distance, plant operational status, and leukemia. Based on the results, the incidence of leukemia in children under 15 years old who lived near operational NPPs is higher than those at farther distance.

Single-cell RNA sequencing provides exciting opportunities to unbiasedly study hematopoiesis. However, our understanding of leukemogenesis was limited due to the high individual differences. Integrated analyses of hematopoiesis and leukemogenesis potentially provides new insights. Here we analyzed ~200,000 single-cell transcriptomes of bone marrow mononuclear cells (BMMCs) and its subsets from 23 clinical samples. We constructed a comprehensive cell atlas as hematopoietic reference. We developed counterpart composite index (CCI; available at GitHub: https://github.com/pengfeeei/cci) to search for the healthy counterpart of each leukemia cell subpopulation, by integrating multiple statistics to map leukemia cells onto reference hematopoietic cells. Interestingly, we found leukemia cell subpopulations from each patient had different healthy counterparts. Analysis showed the trajectories of leukemia cell subpopulations were similar to that of their healthy counterparts, indicating that developmental termination of leukemia initiating cells at different phases leads to different leukemia cell subpopulations thus explained the origin of leukemia heterogeneity. CCI further predicts leukemia subtypes, cellular heterogeneity, and cellular stemness of each leukemia patient. Analyses of leukemia patient at diagnosis, refractory, remission and relapse vividly presented dynamics of cell population during leukemia treatment. CCI analyses showed the healthy counterparts of relapsed leukemia cells were closer to the root of hematopoietic tree than that of other leukemia cells, although single-cell transcriptomic genetic variants and haplotype tracing analyses showed the relapsed leukemia cell were derived from an early minor leukemia cell population. In summary, this study developed a unified framework for understanding leukemogenesis with hematopoiesis reference, which provided novel biological and medical implication. [ABSTRACT FROM AUTHOR]

Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because of their young age. Children with Down syndrome (DS) have an even higher risk of developing leukaemia during the first years of life. The presence of a constitutive trisomy of chromosome 21 (T21) in DS acts as a genetic driver for leukaemia development, however, additional oncogenic mutations are required. Therefore, T21 provides the opportunity to better understand leukaemogenesis in children. Here, we describe the increased risk of leukaemia in DS during childhood from a somatic evolutionary view. According to this idea, cancer is caused by a variation in inheritable phenotypes within cell populations that are subjected to selective forces within the tissue context. We propose a model in which the increased risk of leukaemia in DS children derives from higher rates of mutation accumulation, already present during fetal development, which is further enhanced by changes in selection dynamics within the fetal liver niche. This model could possibly be used to understand the rate-limiting steps of leukaemogenesis early in life. [ABSTRACT FROM AUTHOR]

We conducted a hospital-based case-control study to explore the association between proximity to various land use types and childhood leukemia and lymphoma. This research involved 428 cases of childhood leukemia and lymphoma (2016-2021), along with a control group of 428 children aged 1-15 in Tehran. We analyzed the risk of childhood cancer associated with land use by employing logistic regression adjusted for confounding factors such as parental smoking and family history. The odds ratio (OR) for children with leukemia and lymphoma residing within 100 m of the nearest highway was 1.87 (95% CI = 1.00-3.49) and 1.71 (95% CI = 1.00-2.93), respectively, in comparison to those living at a distance of 1000 m or more from a highway. The OR for leukemia with exposure to petrol stations within 100 m was 2.15 (95% CI = 1.00-4.63), and for lymphoma it was 1.09 (95% CI = 0.47-2.50). A significant association was observed near power lines (OR = 3.05; 95% CI = 0.97-9.55) within < 100 m for leukemia. However, no significant association was observed between power lines and the incidence of childhood lymphoma. There was no association between bus stations, major road class 2, and the incidence of childhood leukemia and lymphoma. In conclusion, our results suggest a possible association between the incidence of childhood leukemia and proximity to different urban land uses (i.e., highways and petrol stations). This study is the first step in understanding how urban land use affects childhood leukemia and lymphoma in Tehran. However, comprehensive studies considering individual-level data and specific pollutants are essential for a more nuanced understanding of these associations., (© 2024. The Author(s).)

Objectives: New epidemiologic approaches are needed to reduce the scientific uncertainty surrounding the association between extremely low frequency magnetic fields (ELF-MF) and childhood leukemia. While most previous studies focused on power lines, the Transformer Exposure study sought to assess this association using a multi-country study of children who had lived in buildings with built-in electrical transformers. ELF-MF in apartments above built-in transformers can be 5 times higher than in other apartments in the same building. This novel study design aimed to maximize the inclusion of highly exposed children while minimising the potential for selection bias., Methods: We assessed associations between residential proximity to transformers and risk of childhood leukemia using registry based matched case-control data collected in five countries. Exposure was based on the location of the subject's apartment relative to the transformer, coded as high (above or adjacent to transformer), intermediate (same floor as apartments in high category), or unexposed (other apartments). Relative risk (RR) for childhood leukemia was estimated using conditional logistic and mixed logistic regression with a random effect for case-control set., Results: Data pooling across countries yielded 16 intermediate and 3 highly exposed cases. RRs were 1.0 (95% CI: 0.5, 1.9) for intermediate and 1.1 (95% CI: 0.3, 3.8) for high exposure in the conditional logistic model. In the mixed logistic model, RRs were 1.4 (95% CI: 0.8, 2.5) for intermediate and 1.3 (95% CI: 0.4, 4.4) for high. Data of the most influential country showed RRs of 1.1 (95% CI: 0.5, 2.4) and 1.7 (95% CI: 0.4, 7.2) for intermediate (8 cases) and high (2 cases) exposure., Discussion: Overall, evidence for an elevated risk was weak. However, small numbers and wide confidence intervals preclude strong conclusions and a risk of the magnitude observed in power line studies cannot be excluded., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: XPV is a former employee of the Electric Power Research Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Leukemia is the most common cancer in children. Its incidence has been increasing worldwide since 1910th, suggesting the presence of common sources of the disease, most likely related to people's lifestyle and environment. Understanding the relationship between childhood leukemia and environmental conditions is critical to preventing the disease. This discussion article examines established potentially-carcinogenic environmental factors, such as vehicle emissions and fires, alongside space weather-related parameters like cosmic rays and the geomagnetic field. To discern the primary contributor, we analyze trends and annual variations in leukemia incidence among 0-14-year-olds in the United States, Canada, Australia, and Russia from 1990 to 2018. Comparisons are drawn with the number of vehicles (representing gasoline emissions) and fire-affected land areas (indicative of fire-related pollutants), with novel data for Russia introduced for the first time. While childhood leukemia incidence is rising in all countries under study, the rate of increase in Russia is twice that of other nations, possibly due to a delayed surge in the country's vehicle fleet compared to others. This trend in Russia may offer insights into past leukemia levels in the USA, Canada, and Australia. Our findings highlight vehicular emissions as the most substantial environmental hazard for children among the factors examined. We also advocate for the consideration of potential modulation of carcinogenic effects arising from variations in cosmic ray intensity, as well as the protective role of the geomagnetic field. To support the idea, we provide examples of potential space weather effects at both local and global scales. The additional analysis includes statistical data from 49 countries and underscores the significance of the magnetic field dip in the South Atlantic Anomaly in contributing to a peak in childhood leukemia incidence in Peru, Ecuador and Chile. We emphasize the importance of collectively assessing all potentially carcinogenic factors for the successful future predictions of childhood leukemia risk in each country., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Khabarova, Pinaev, Chakov, Chizhov and Pinaeva.)

Introduction: Leukemia relapse following stem cell transplantation remains a significant barrier to long-term remission. Timely and balanced immune recovery after transplantation is crucial for preventing leukemia relapse., Areas Covered: After an extensive literature search of PubMed and Web of Science through October 2023, we provide an overview of the dynamics of immune reconstitution and its role in controlling leukemia relapse. We also discuss strategies to promote immune reconstitution and reduce disease recurrence following allogeneic hematopoietic stem cell transplantation., Expert Opinion: Immune reconstitution after transplantation has substantial potential to prevent relapse and might predict disease recurrence and prognosis. High dimensional cytometry, multi-omics, and T cell repertoire analysis allow for a more comprehensive and detailed understanding of the immune system's dynamics post-transplantation, and contribute to the identification of rare immune cell subsets or potential biomarkers associated with successful immune reconstitution or increased risk of complications. Strategies to enhance the immune system, such as adoptive immunotherapy and cytokine-based therapy, have great potential for reducing leukemia relapse after transplantation. Future research directions should focus on refining patient selection for these therapies, implementing appropriate and timely treatment, investigating combination approaches to maximize therapeutic outcomes, and achieving a robust graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD) for optimal results.

Leukemias are a set of clonal hematopoietic malignant diseases that develop in the bone marrow. Several factors influence leukemia development and progression. Among these, the gut microbiota is a major factor influencing a wide array of its processes. The gut microbial composition is linked to the risk of tumor development and the host's ability to respond to treatment, mostly due to the immune-modulatory effects of their metabolites. Despite such strong evidence, its role in the development of hematologic malignancies still requires attention of investigators worldwide. In this review, we make an effort to discuss the role of host gut microbiota-immune crosstalk in leukemia development and progression. Additionally, we highlight certain recently developed strategies to modify the gut microbial composition that may help to overcome dysbiosis in leukemia patients in the near future., Competing Interests: Conflicts of Interest Disclosure The authors declare no competing financial interests., (Copyright © 2024 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Introduction: Since malignancy during pregnancy is uncommon, information regarding contraception selection or sterilization at delivery is limited. The objective of this study was to examine the type of long-acting reversible contraception or surgical sterilization procedure chosen by pregnant patients with malignancy at delivery., Material and Methods: This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample in the USA. The study population was vaginal and cesarean deliveries in a hospital setting from January 2017 to December 2020. Pregnant patients with breast cancer (n = 1605), leukemia (n = 1190), lymphoma (n = 1120), thyroid cancer (n = 715), cervical cancer (n = 425) and melanoma (n = 400) were compared with 14 265 319 pregnant patients without malignancy. The main outcome measures were utilization of long-acting reversible contraception (subdermal implant or intrauterine device) and performance of permanent surgical sterilization (bilateral tubal ligation or bilateral salpingectomy) during the index hospital admission for delivery, assessed with a multinomial regression model controlling for clinical, pregnancy and delivery characteristics., Results: When compared with pregnant patients without malignancy, pregnant patients with breast cancer were more likely to proceed with bilateral salpingectomy (adjusted odds ratio [aOR] 2.30) or intrauterine device (aOR 1.91); none received the subdermal implant. Pregnant patients with leukemia were more likely to choose a subdermal implant (aOR 2.22), whereas those with lymphoma were more likely to proceed with bilateral salpingectomy (aOR 1.93) and bilateral tubal ligation (aOR 1.76). Pregnant patients with thyroid cancer were more likely to proceed with bilateral tubal ligation (aOR 2.21) and none received the subdermal implant. No patients in the cervical cancer group selected long-acting reversible contraception, and they were more likely to proceed with bilateral salpingectomy (aOR 2.08). None in the melanoma group chose long-acting reversible contraception. Among pregnant patients aged <30, the odds of proceeding with bilateral salpingectomy were increased in patients with breast cancer (aOR 3.01), cervical cancer (aOR 2.26) or lymphoma (aOR 2.08). The odds of proceeding with bilateral tubal ligation in pregnant patients aged <30 with melanoma (aOR 5.36) was also increased., Conclusions: The results of this nationwide assessment in the United States suggest that among pregnant patients with malignancy, the preferred contraceptive option or method of sterilization at time of hospital delivery differs by malignancy type., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Several studies have documented an increased risk of leukemia among children exposed to magnetic fields from high-voltage power lines, with some evidence of dose-response relation. However, findings in some studies have been inconsistent, and data on the effects of different sources of exposure are lacking. In this study, we evaluated the relation of childhood leukemia risk to exposure to magnetic fields from transformer stations., Methods: We conducted a population-based case-control study in a pediatric population of two Northern Italian provinces of Modena and Reggio Emilia. We included 182 registry-identified childhood leukemia cases diagnosed during 1998-2019 and 726 population controls matched on sex, year of birth, and province of residence. We assessed exposure by calculating distance from childhood residence to the nearest transformer station within a geographical information system, computing disease odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for potential confounders. We evaluated exposure using two buffers (15 m and 25 m radius) and assessed two case groups: leukemia (all subtypes) and acute lymphoblastic leukemia (ALL)., Results: Residing within 15 m of a transformer station (vs. ≥15 m) was not appreciably associated with risk of leukemia (all subtypes) or ALL. We found similar results using a less stringent exposure buffer (25 m). Among children aged ≥5 years, the adjusted ORs were 1.3 (95% CI 0.1-12.8) for leukemia and 1.3 (95% CI 0.1-12.4) for ALL using the 15 m buffer, while they were 1.7 (95% CI 0.4-7.0) for leukemia and 0.6 (95% CI 0.1-4.8) for ALL using the 25 m buffer., Conclusions: While we found no overall association between residential proximity to transformer stations and childhood leukemia, there was some evidence for elevated risk of childhood leukemia among children aged ≥5 years. Precision was limited by the low numbers of exposed children., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Wise is a consultant for AbbVie Inc, and the Gates Foundation. Her institution also receives NIH funding for studies outside of this work. Finally, Dr. Wise receives in-kind donations for primary data collection in the PRESTO cohort (Swiss Precision Diagnostics and Kindara.com). All other authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients., (© 2023 World Obesity Federation.)

Background: Acute leukemia is the most common pediatric cancer, with an incidence peak at 2-5 years of age. Despite the medical advances improving survival rates, children suffer from significant side effects of treatments as well as its high social and economic impact. The frequent prenatal origin of this developmental disease follows the two-hit carcinogenesis model established in the 70s: a first hit in prenatal life with the creation of genetic fusion lesions or aneuploidy in hematopoietic progenitor/stem cells, and usually a second hit in the pediatric age that converts the preleukemic clone into clinical leukemia. Previous research has mostly focused on postnatal environmental factors triggering the second hit., Summary: There is scarce evidence on prenatal risk factors associated with the first hit. Mainly retrospective case-control studies suggested several environmental and lifestyle determinants as risk factors. If these associations could be confirmed, interventions focused on modifying prenatal factors might influence the subsequent risk of leukemia during childhood and reveal unexplored research avenues for the future. In this review, we aim to comprehensively summarize the currently available evidence on prenatal risk factors for the development of childhood leukemia. According to the findings of this review, parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Other factors such as socioeconomic status, consumption of caffeinated beverages, and smoking consumption have been suggested with inconclusive evidence. Additionally, investigating the association between prenatal factors and genetic lesions associated with childhood leukemia at birth is crucial. Prospective studies evaluating the link between lifestyle factors and genetic alterations could provide indirect evidence supporting new research avenues for leukemia prevention. Maternal diet and lifestyle factors are modifiable determinants associated with adverse perinatal outcomes that could be also related to preleukemic lesions., Key Messages: Parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Dedicating efforts to studying maternal lifestyle during pregnancy and its association with genetic lesions leading to childhood leukemia could lead to novel prevention strategies., (© 2024 S. Karger AG, Basel.)

Leukemia is a rapidly progressive disease which is one of the most common causes of death worldwide. Several therapy modalities have been employed in the treatment of leukemia such as natural anticancer compounds which found in plants e.g. Saussurea Lappa (S. lappa). To determine cytotoxic activity of S. lappa extracts in relation to CCAAT/Enhancer Binding Protein Alpha (C/EBPA) gene expression, in addition to phytochemical analysis and antioxidant activity. Successive extraction of S. lappa root powder using methanol, ethanol, acetone, ethyl acetate and chloroform solvents with separation of twelve fractions from chloroform extract by thin layer chromatography (TLC). Estimation of total phenolic and total flavonoid were done together with antioxidant, cytotoxic activity of S. lappa extracts which has been tested on three leukemia cell cultures by MTT assay. C/EBPA gene expression was detected by quantitative real time PCR (qRT-PCR). The chloroform extract of S. lappa showed the highest cytotoxic activity against three cancer cell cultures. Regarding C/EBPA gene expression in leukemic cells after addition of chloroform fractions (C2+C9) from the S. lappa plant, we found a statistically significant difference (P value 0.008) with (C9) compound; this denotes the higher cytotoxic activity of (C9) on the leukemia cells. The S. lappa roots contain phenol and flavonoid compounds, which have a high cytotoxic effect on leukemic cells and improve CEBPA gene expression which is a known good prognostic marker. Further studies of S. lappa for the elucidation of the cytotoxic mechanisms considered as immense importance to deal with leukemia. [ABSTRACT FROM AUTHOR]

Disease caused by bovine leukemia virus (BLV) results in significant economic losses to the livestock industry. To date, there is only one report describing the strains found in Italy. BLV strains (n = 24), collected between 2012 and 2016 from four different Italian regions, were genetically analyzed by direct sequencing of a portion of the BLV env gene, and the sequences were compared with those in the GenBank database. The Italian BLVs clustered into genotypes G2, G4, G6, G7, and G8, revealing a high level of BLV genetic heterogeneity in Italy. This study provides a basis for further investigations into the evolutionary relationship between BLV strains. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a common cancer cell phenotype as it sustains growth and proliferation. Targeting metabolic activities offers a wide range of therapeutic possibilities which are applicable to acute myeloid leukemia (AML). Indeed, in addition to the IDH1/2-mutated AML model which established the proof-of-concept for specifically targeting metabolic adaptations in AML, several recent reports have expanded the scope of such strategies in these diseases. This review highlights recent findings on metabolic deregulation in AML and summarizes their implications in leukemogenesis. [ABSTRACT FROM AUTHOR]

Abstract The BCR-ABL1 oncogene is associated with chronic myeloid leukemia (CML) pathogenesis, but the molecular mechanisms that initiate leukemogenesis are still unclear. Cancer pathogenesis has been associated with genetic alterations that may lead to inactivation of tumor suppressor genes. Phosphatase and tensin homolog (PTEN) is frequently deleted or inactivated in various tumors. A recently discovered variant of PTEN, PTEN-Long (PTEN-L), results from an alternative translation initiation site located upstream of the canonic AUG and generates a protein of 576 amino acids instead the expected protein of 403 amino acids. A 16 bp perfect palindromic motif centered on the PTEN-L CUG513 start codon is required for translation initiation. A single nucleotide polymorphism (SNP) of PTEN-L gene rs12573787 is located on the first exon respect to the CUG initiation site. In this case-control study we evaluated the association of genetic variants in PTEN-L with CML risk and therapy response in the Argentine population. The allele A of SNP rs12573787 was found to be associated with CML risk OR (95% CI) 1.71 (1.11–2.63) p = 0.016, which resulted consistent by multivariate analysis adjusted by gender and age. According to previous evidence that CML is more frequent in males, we found that the genetic risk of CML was confined to this gender. Unexpectedly, we also found this association confined to CML patients older than 45 years old. To our knowledge, this is the first time that PTEN-L rs1257378 was studied in CML suggesting that the variant A allele is a risk factor for CML development but, no association with the failure to TKIs treatment was found. Highlights • This is the first report that assesses the PTEN-long SNP rs12573787 in CML risk and outcome. • Variant A allele and genotypes (G/A + A/A) were associated with CML risk. • Males and older patients with variant genotypes exhibited an increased CML risk. • No association with the response to TKIs treatment was found. • Argentine alleles frequencies fit with those reported worldwide, but differ from East Asians. [ABSTRACT FROM AUTHOR]

B-cell lymphoma/leukemia 11B (Bcl11b) is a transcription factor critical for thymocyte development. We have previously characterized the kinetic post-translational modifications (PTMs) of Bcl11b in double-positive (DP) thymocytes during stimulation of the T cell receptor-activated MAP kinase pathway. However, the PTMs of Bcl11b in thymocytes from other developmental stages in the thymus, primarily double-negative (DN) cells, have not been previously identified. We found that kinetic modifications of Bcl11b in DN cells are somewhat different than the patterns observed in DP cells. Distinct from DP thymocytes, phosphorylation and sumoylation of Bcl11b in DN cells were not oppositely regulated in response to activation of MAP kinase, even though hyper-phosphorylation of Bcl11b coincided with near complete desumoylation. Additionally, prolonged stimulation of the MAP kinase pathway in DN cells, unlike DP thymocytes, did not alter Bcl11b levels of sumoylation or ubiquitinylation, or stability. On the other hand, activation of Wnt–Gsk3-dependent signaling in DN cells resulted in composite dephosphorylation and sumoylation of Bcl11b. Moreover, stimulation of MAP kinase and (or) Wnt signaling pathways differentially affects gene expression of some Bcl11b target and maturation-associated genes. Defining the signaling pathways and regulation of sequence-specific transcription factors by PTMs at various stages of thymopoiesis may improve our understanding of leukemogenesis. [ABSTRACT FROM AUTHOR]

Eukaryotic DNA methylation prevents genomic instability by regulating the expression of oncogenes and tumor-suppressor genes. The negative effects of dysregulated DNA methylation are highlighted by a strong correlation between mutations in the de novo DNA methyltransferase gene DNA methyltransferase 3- (DNMT3A) and poor prognoses among acute myeloid leukemia (AML) patients. We show here that clinically observed DNMT3A mutations dramatically alter enzymatic activity, including mutations that lead to 6-fold hypermethylation and 3-fold hypomethylation of the human cyclin-dependent kinase inhibitor 2B (CDKN2B or p15) gene promoter. Our results provide insights into the clinically observed heterogeneity of p15 methylation in AML. Cytogenetically normal AML (CN-AML) constitutes 40-50% of all AML cases and is the most epigenetically diverse AML subtype with pronounced changes in non-CpG DNA methylation. We identified a subset of DNMT3A mutations that enhance the enzyme's ability to perform non-CpG methylation by 2-8-fold. Many of these mutations mapped to DNMT3A regionsknownto interact with proteins that themselves contribute toAML,suchasthymineDNAglycosylase(TDG).Usingfunctional mapping of TDG-DNMT3A interactions, we provide evidence that TDG and DNMT3-like (DNMT3L) bind distinct regions of DNMT3A. Furthermore, DNMT3A mutations caused diverse changes in the ability of TDG and DNMT3L to affect DNMT3A function. Cell-based studies of one of these DNMT3A mutations (S714C) replicated the enzymatic studies and revealed that it causes dramatic losses of genome-wide methylation. In summary, mutations in DNMT3A lead to diverse levels of activity, interactions with epigenetic machinery components and cellular changes. [ABSTRACT FROM AUTHOR]

The vital role of long noncoding RNAs (lncRNAs) on the acute myeloid leukemia (AML) has been increasingly recognized. This study aims to explore the unknown function of lncRNA LINC00152 in the leukemogenesis of AML. LINC00152 is determined to be upregulated in the AML samples, and the overexpression of LINC00152 is also authenticated in the advanced French–American–British (FAB) AML patients and closely correlated with the poor outcome of AML patients. The functional experiments state that knockdown of LINC00152 suppresses the proliferation, accelerates the apoptosis, and induces the cycle arrest of AML cells. The mechanical experiments state that LINC00152 and CDK9 were both targeted by miR-193a with the complementary binding sites at 3′-UTR. Moreover, in the rescue experiments, the enhanced LINC00152 expression could regain the suppression of tumor behavior induced by LINC00152 knockdown. In conclusion, this research reveals the important role of lncRNA LINC00152 in the AML leukemogenesis through targeting miR-193a/CDK9 axis. This finding could indicate the important pathogenesis of ncRNA and the vital roles of epigenetic regulation. [ABSTRACT FROM AUTHOR]

Abstract Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. The acquired Janus kinase 2 (JAK2) K607N somatic mutation was detected in about 6.8% of acute myeloid leukemia (AML) patients. However, roles of JAK2 K607N mutation in the leukemogenesis of AML remain unclear. In this study, loss of interaction between K607 and E877 was identified as key reasons for JAK2 K607N mutation constitutive activation. JAK2 K607N and mutations (K607A, K607G and E877A) abolished the K607 and E877 interaction caused JAK2 constitutive activation. While, mutations (K607R, E877D) repairing this interaction reduced K607N mutation's activity. Furthermore, our studies showed that disruption of K607 and E877 interaction abolished JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, JAK2 K607N and mutations disrupted this interaction enhanced JAK2-STAT5 pathway activation and the proliferation of Ba/F3 cells. Thus our studies provide clues in understanding the leukemogenesis of JAK2 K607N mutation in AML. [ABSTRACT FROM AUTHOR]

High frequency of acquired CSF3R (colony stimulating factor 3 receptor, granulocyte) mutations has been described in patients with severe congenital neutropenia (CN) at pre-leukemia stage and overt acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Here, we report the establishment of an ultra-sensitive deep sequencing of a CSF3R segment encoding the intracellular "critical region" of the G-CSFR known to be mutated in CN-MDS/AML patients. Using this method, we achieved a mutant allele frequency (MAF) detection rate of 0.01%. We detected CSF3R mutations in CN patients with different genetic backgrounds, but not in patients with other types of bone marrow failure syndromes chronically treated with G-CSF (e.g., Shwachman-Diamond Syndrome). Comparison of CSF3R deep sequencing results of DNA and cDNA from the bone marrow and peripheral blood cells revealed the highest sensitivity of cDNA from the peripheral blood polymorphonuclear neutrophils. This approach enables the identification of low-frequency CSF3R mutant clones, increases sensitivity, and earlier detection of CSF3R mutations acquired during the course of leukemogenic evolution of pre-leukemia HSCs of CN patients. We suggest application of sequencing of the entire CSF3R gene at diagnosis to identify patients with inherited lost-of-function CSF3R mutations and annual ultra-deep sequencing of the critical region of CSF3R to monitor acquisition of CSF3R mutations. [ABSTRACT FROM AUTHOR]

SALL4 is a transcription factor that retains stem cells in an undifferentiated state and promotes its self-renewal. In addition, it is implicated in leukemogenesis via its effect on leukemic stem cells. This study aimed to characterize the expression pattern of SALL4 gene in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) at different progression phases of the leukemic process and to assess its prognostic significance. Real-time PCR was used in 106 patients: 54 AML patients; 43 de novo and 11 in complete remission (CR), 52 CML patients; 31 in chronic phase (CP), 11 in deep molecular response (MR4) and 10 in accelerated/blastic phase (AP/BP); and in 21 nonmalignant bone marrow samples. SALL4 gene expression was elevated in AML, AML-CR and CML-CP (median = 5.180, 4.604 and 14.125 fold changes, respectively). Elevated SALL4 gene expression among AML de novo patient was associated with poor disease-free survival (DFS) rates (p = .022). Among CML patients, the highest percentage of patients with a high SALL4 (p = .033) was among CML-CP. SALL4 has a role in leukemogenesis; high SALL4 expression was associated with poor DFS among AML patients. [ABSTRACT FROM AUTHOR]

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO- containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNAbinding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1- ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2- 2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2- 2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Leukemia is the most prevalent cancer among children and adolescents. This study investigated the potential association between exposure to magnetic fields and the risk of pediatric leukemia., Methods: We conducted a comprehensive search of electronic databases, including Scopus, EMBASE, Cochrane, Web of Science, and Medline, up to December 15, 2022, to identify relevant studies examining the link between childhood leukemia and magnetic field exposure., Results: The first meta-analysis revealed a statistically significant inverse association between pediatric leukemia and magnetic field strengths ranging from 0.4 μT to 0.2 μT, suggesting a reduced risk associated with this range. The second meta-analysis focused on wiring configuration codes and observed a potential link between residential magnetic field exposure and childhood leukemia. Pooled relative risk estimates were 1.52 (95% CI = 1.05-2.04, P = .021) and 1.58 (95% CI = 1.15-2.23, P = .006) for exposure to 24-hour magnetic field measurements, suggesting a possible causal relationship. In the third meta-analysis, the odds ratios for the exposure groups of 0.1 to 0.2 μT, 0.2 to 0.3 μT, 0.3 to 0.4 μT, and 0.4 μT above 0.2 μT were 1.09 (95% confidence interval = 0.82 to 1.43 μT), 1.14 (95% confidence interval = 0.68 to 1.92 μT), and 1.45 (95% confidence interval = 0.87 to 2.37 μT), respectively. In contrast to the findings of the three meta-analyses, there was no evidence of a statistically significant connection between exposure to 0.2 μT and the risk of juvenile leukemia. A further result showed no discernible difference between the two groups of children who lived less than 100 meters from the source of magnetic fields and those who lived closer (OR = 1.33; 95% CI = 0.98-1.73 μT)., Conclusions: The collective results of three meta-analyses, encompassing magnetic field strengths ranging from 0.1 μT to 2.38 μT, underscore a statistically significant association between the intensity of magnetic fields and the occurrence of childhood leukemia. However, one specific analysis concluded that no apparent relationship exists between exposure to 0.1 μT and an elevated risk of leukemia development in children.

ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations. [ABSTRACT FROM AUTHOR]

Highlights • We provide a comparison of engraftment efficiencies in unconditioned NRG (NOD/RAG1/2−/−IL2Rγ−/−) and NRGS (NRG-SGM3) mice. • NRGS mice do not develop clinically accurate disease with cell line xenografts. • NRG mice do not efficiently engraft patient normal or leukemic cells. • NRG and NRGS mice tolerate high doses of induction therapeutics. Cell-line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) in immune-deficient mice have revolutionized our understanding of normal and malignant human hematopoiesis. Transgenic approaches further improved in vivo hematological research, allowing the development of human-cytokine-producing mice, which show superior human cell engraftment. The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdcscid Il2rγtm1Sug/Jic) and the NSG (NOD/SCID-IL2Rγ−/−, NOD.Cg-PrkdcscidIl2rγtm1Wjl/SzJ) mouse, and their human-cytokine-producing (interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor) counterparts (huNOG and NSGS), rely partly on a mutation in the DNA repair protein PRKDC, causing a severe combined immune deficiency (SCID) phenotype and rendering the mice less tolerant to DNA-damaging therapeutics, thereby limiting their usefulness in the investigation of novel acute myeloid leukemia (AML) therapeutics. NRG (NOD/RAG1/2−/−IL2Rγ−/−) mice show equivalent immune ablation through a defective recombination activation gene (RAG), leaving DNA damage repair intact, and human-cytokine-producing NRGS (NRG-SGM3) mice were generated, improving myeloid engraftment. Our findings indicate that unconditioned NRG and NRGS mice can harbor established AML CDXs and can tolerate aggressive induction chemotherapy at higher doses than NSG mice without overt toxicity. However, unconditioned NRGS mice developed less clinically relevant disease, with CDXs forming solid tumors throughout the body, whereas unconditioned NRG mice were incapable of efficiently supporting PDX or human hematopoietic stem cell engraftment. These findings emphasize the contextually dependent utility of each of these powerful new strains in the study of normal and malignant human hematopoiesis. Therefore, the choice of mouse strain cannot be random, but must be based on the experimental outcomes and questions to be addressed. [ABSTRACT FROM AUTHOR]

Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naïve B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B-cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation. [ABSTRACT FROM AUTHOR]

Mutations of ASXL1 are early events in acute myeloid leukemia (AML) leukemogenesis and have been associated with unfavorable prognosis. In this study, we investigated the type and frequency of ASXL1 mutations in a large cohort of patients with de novo or secondary AML (s-AML) and looked for correlations with cytogenetic findings and disease features. ASXL1 mutations were associated with older age, s-AML and higher peripheral leukocytosis. We observed more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations but a negative correlation with myelodysplastic syndromes (MDS)-related cytogenetic abnormalities, especially −5/del(5q) and −7/del(7q). ASXL1 mutations were also found in other genetically defined AML subgroups such as those with t(9;22), inv(3)/t(3;3), t(8;21) or t(15;17); however, none of our inv(16) cases carried ASXL1 mutations. We detected two previously unreported ASXL1 mutations, p.IIe593Val and p.Cys688Tyr. Our findings suggest that ASXL1 mutations tend to cluster with specific clinical and cytogenetic profiles of AML patients. [ABSTRACT FROM AUTHOR]

The human T cell leukemia virus I basic leucine zipper protein (HTLV-1 HBZ) maintains chronic viral infection and promotes leukemogenesis through poorly understood mechanisms involving interactions with the KIX domain of the transcriptional coactivator CBP and its paralog p300. The KIX domain binds regulatory proteins at the distinct MLL and c-Myb/pKID sites to form binary or ternary complexes. The intrinsically disordered N-terminal activation domain of HBZ (HBZ AD) deregulates cellular signaling pathways by competing directly with cellular and viral transcription factors for binding to the MLL site and by allosterically perturbing binding of the transactivation domain of the hematopoietic transcription factor c-Myb. Crystal structures of the ternary KIX:c-Myb:HBZ complex show that the HBZ AD recruits two KIX: c-Myb entities through tandem amphipathic motifs (L/V)(V/L)DGLL and folds into a long α-helix upon binding. Isothermal titration calorimetry reveals strong cooperativity in binding of the c-Myb activation domain to the KIX:HBZ complex and in binding of HBZ to the KIX:c-Myb complex. In addition, binding of KIX to the two HBZ (V/L)DGLL motifs is cooperative; the structures suggest that this cooperativity is achieved through propagation of the HBZ α-helix beyond the first binding motif. Our study suggests that the unique structural flexibility and the multiple interaction motifs of the intrinsically disordered HBZ AD are responsible for its potency in hijacking KIX-mediated transcription pathways. The KIX: c-Myb:HBZ complex provides an example of cooperative stabilization in a transcription factor:coactivator network and gives insights into potential mechanisms through which HBZ dysregulates hematopoietic transcriptional programs and promotes T cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Most cases of acute leukemia arise without identifiable risk factors. Studies investigating the impact of autoimmune diseases and infections on leukemogenesis have revealed conflicting results. If inflammation increases the risk of acute myeloid leukemia (AML), ­nonsteroidal anti-inflammatory drug (NSAID) use may decrease the risk of leukemia.Methods: We conducted a case-control study of 3,053 patients with AML diagnosed between 2000 and 2013, who were registered in the Danish National Acute Leukemia Registry, and 30,530 population controls matched on sex and age. We identified prescriptions through the Danish National Health Service Prescription Database. We used conditional logistic regression analysis to compute ORs associating AML with NSAID use overall, in patients with inflammatory diseases, and for specific AML subtypes (de novo AML, AML related to previous hematological disease, ie, secondary AML [sAML], or therapy-related AML [tAML; exposed to previous cytotoxic therapy]).Results: Overall, NSAID use was not associated with a lower risk of AML (OR 1.1, 95% CI=1.0–1.2), de novo AML (OR 1.0, 95% CI=0.9–1.1), and sAML/tAML (OR 1.3, 95% CI=1.1–1.5). In addition, in patients with known inflammatory diseases, NSAIDs did not affect AML risk (OR 0.9, 95% CI=0.5–1.6). Number of prescriptions, type of NSAID, age, or sex did not influence the results.Conclusion: In line with our recent findings that showed no association between autoimmune diseases and infections and de novo AML, NSAID use was not found to reduce the risk of AML. [ABSTRACT FROM AUTHOR]

Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms' tumor 1 (WT1) gene. The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady-state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, which increased stem cell function over time and resulted in age-dependent leukemic transformation. Wt1-haplo insufficient leukemias were characterized by progressive genetic and epigenetic alteraions, including those in known leukemia-associated alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that Wt1 depletion cooperates with Flt3-ITD mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of Wt1-loss leukemogenesis and into the evolutionary events required to induce transformation of Wt1-haploinsufficient stem/progenitor cells. [ABSTRACT FROM AUTHOR]

TSC (tuberous sclerosis) complex is the major negative regulator of mTOR which activates cell cycle progression leading to uncontrolled growth. Acute leukemias are very heterogeneous as a group of hematological malignancies; they arise as a result of pled up genetic alterations. To study TSC gene expression in acute leukemia patients. Sixty-two Egyptian de no novo adult acute leukemia patients were assessed using SYBR green quantitative PCR as well as 22 controls. Correlation of TSC gene expression with response rate, other prognostic factors, and RFS was assessed. TSC1/TSC2 showed higher gene expression in acute leukemias compared to controls. TSC1 was significantly higher in T-ALL while TSC2 was significantly higher in B-ALL. Expression did not show significant correlation to known prognostic factors. TSC1/TSC2 overexpression might be implicated in the process of leukemogenesis. [ABSTRACT FROM AUTHOR]

Recurrent non-random chromosomal translocations are hallmark characteristics of leukemogenesis, and however, molecular mechanisms underlying these rearrangements are less explored. The fundamental question is, why and how chromosomes break and reunite so precisely in the genome. Meticulous understanding of mechanism leading to chromosomal rearrangement can be achieved by characterizing breakpoints. To address this hypothesis, a novel multi-parametric computational approach for characterization of major leukemic translocations within and around breakpoint region was performed. To best of our knowledge, this bioinformatic analysis is unique in finding the presence of segmental duplications (SDs) flanking breakpoints of all major leukemic translocation. Breakpoint islands (BpIs) were analyzed for stress-induced duplex destabilization (SIDD) sites along with other complex genomic architecture and physicochemical properties. Our study distinctly emphasizes on the probable correlative role of SDs, SIDD sites and various genomic features in the occurrence of breakpoints. Further, it also highlights potential features which may be playing a crucial role in causing double-strand breaks, leading to translocation. [ABSTRACT FROM AUTHOR]

Abstract: The impact of LMO2 expression on cell lineage decisions during T‐cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T‐cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human‐like T‐ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T‐ALL. The resulting T‐ALLs lacked LMO2 and its target‐gene expression, and histologically, transcriptionally, and genetically similar to human LMO2‐driven T‐ALL. We next found that during T‐ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T‐ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre‐mediated activation of Lmo2 at different stages of B‐cell development induces systematically and unexpectedly T‐ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T‐ALL to current therapies. [ABSTRACT FROM AUTHOR]

PAX5 mutations have important role in leukemogenesis and leukemia relapse, cancer cell dormancy participates in cancer relapse, but there was no report about PAX5 mutation inducing cancer cell dormancy. we constructed the PAX5 deletion Raji cell lines using gene editing technology, evaluated dormancy biological characteristics of cell lines. Our results showed PAX5 haploinsufficiency restrained the proliferation of Raji cells, induced G0/G1 arrest of Raji cells, reduced chemotherapy sensitivity. The tumor formation rate reduced in PAX5 mutation Raji cells. Our results showed PAX5 insufficiency induced cancer cell dormancy in Raji cell. [ABSTRACT FROM AUTHOR]

Objective: An increasing amount of evidence shows that childhood leukemia is initiated in utero. Birth characteristics initiated in utero, such as gestational age, may play a role in leukemogenesis. The purpose of our meta-analysis is to explore the association between gestational age and childhood leukemia. Methods: Relevant studies up to 21 April 2017 were collected by searching PubMed and EMBASE databases. Subgroup analysis, sensitivity analysis and publication bias assessment were conducted. Results: A total of 13 studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for preterm birth and postterm birth were 1.06 (0.98, 1.13) and 1.01 (0.90, 1.13) for childhood leukemia, 1.04 (0.97, 1.11) and 1.03 (0.95, 1.12) for acute lymphocytic leukemia (ALL), 1.20 (1.00, 1.44) and 1.20 (1.00, 1.43) for acute myeloid leukemia (AML), compared with full-term birth. Study type and study region were the reasons behind the heterogeneity. In subgroup analyses, the summary ORs with 95% CI for childhood leukemia and ALL were 1.23 (1.07, 1.41) and 1.21 (1.06, 1.39) for postterm birth in cohort studies. No significant changes in sensitivity analyses and no publication bias were observed in our analysis. Conclusion: Our results suggest that both preterm and postterm infants have an elevated risk of developing AML. In addition, postterm birth increased the risk of childhood leukemia and ALL in cohort studies. However, more studies are warranted to validate these results and explore the biologic mechanisms underlying these relationships. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia is a hematopoietic malignant disease, which arises from a genetic defect in the T-cell maturation signaling pathway. As a result, it is necessary to identify the molecules that impact T-cell development and control lymphoid-lineage malignancy. The present study utilized Jurkat T lymphoblastic cells as a well-established approach for the investigation into the function of the non-canonical alternative splice variant of Helios for the in vitro study of T-cell differentiation and leukemogenesis. In the present study, the Jurkat T-cell lines with stable overexpression of the wild-type (Helios-1) or the non-canonical short isoform (Helios-Δ326-1431), were established. RNA microarray, reverse transcription-quantitative polymerase chain reaction and flow cytometry were used to assess changes in the gene expression profiles and to monitor the cell surface markers during T-cell differentiation. Multiple genes associated with T-cell differentiation and leukemogenesis were identified as being either activated or suppressed. In addition, the results indicated that the stable overexpression of the Helios isoforms stimulated the differentiation pathway of the T-lineage lymphoblastic cells. Therefore, these results suggest that full-length Helios-1 has a tumor suppressor-like and immunomodulatory role, in contrast to the oncogenic function of the non-canonical short isoform Helios-Δ326-1431. [ABSTRACT FROM AUTHOR]

The adult adaptive immune system is comprised of a wide spectrum of lymphocyte subsets with distinct antigen receptor repertoire profiles, effector functions, turnover times and anatomical locations, acting in concert to provide optimal host protection and self-regulation. While some lymphocyte populations are replenished by bone marrow hematopoietic stem cells (HSCs) through adulthood, others emerge during a limited window of time during fetal and postnatal life and sustain through self-replenishment. Despite fundamental implications in immune regeneration, early life immunity and leukemogenesis, the impact of developmental timing on lymphocyte output remains an under explored frontier in immunology. In this review, we spotlight recent insights into the developmental changes in B cell output in mice and explore how several age specific cellular and molecular factors may shape the formation of a diverse adaptive immune system. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRs) have been demonstrated to perform important roles in normal hematopoiesis and leukemogenesis. Accumulating evidence suggests that miR-10a and miR-10b may behave as novel oncogenes or tumor suppressors in human cancer. The present study reported the function of the miR-10 family in myeloid differentiation and acute myeloid leukemia (AML). The levels of miR-10a/b expression were increased in AML cases compared with normal controls, particularly in M1, M2 and M3 subtypes. The levels of miR-10a/b expression were also upregulated in patients with nucleophosmin-mutated AML and AML patients with t(8;21) and t(9;11), compared with the normal control. In addition, the role of miR-10a/b in regulating myeloid differentiation and leukemogenesis was investigated. The results indicated that miR-10a/b expression was able to promote the proliferation of human promyelocytic leukemia cells, while suppressing the granulocytic and monocytic differentiation of the leukemia cells. These findings suggested that abnormal high expression of miR-10a/b may result in unlimited proliferation of immature blood progenitors and repression of mature blood cell differentiation and maturation, thus leading to the occurrence of AML. miR-10a/b may be developed as novel therapeutic targets for the treatment of AML. [ABSTRACT FROM AUTHOR]