Risk Of Leukemia Research Articles

APEX1 Polymorphisms Affect Acute Myeloid Leukemia Risk, and Its Expression Is Involved in Cell Proliferation and Differentiation.

The link between DNA repair gene polymorphisms and cancer susceptibility has gained significant attention. Thus, we investigated the impact of base excision repair (BER) gene polymorphisms on acute myeloid leukemia (AML) risk and pathogenesis. In total, 106 patients with AML and 191 healthy controls were included in the study, wherein polymorphisms in four BER genes (APEX1, MUTYH, OGG1, and XRCC1) were examined. Notably, the APEX1-656 T>G polymorphism exhibited a significant association with AML risk in the recessive (TT vs. TG + GG) (p = 0.046) and co-dominant models (TT vs. GG) (p = 0.02). Assessing APEX1 expression levels, APEX1 expression was elevated in the bone marrow of patients with AML compared with that in controls (p = 0.02). Subsequently, we compared the percentages of CD34+ cells between the APEX1 high or low expression groups, revealing a significant difference (high vs. low = 29.9% vs. 11.5%, p = 0.01). Additionally, we observed reduced APEX1 expression in HL60 cells differentiated with all-trans retinoic acid (p < 0.001). We hypothesized that APEX1 expression could correlate with stemness and analyzed its expression in stem and differentiated cells. In the GSE48558 dataset, AML cells and normal CD34+ cells expressed APEX1 at higher levels than did granulocytes (p < 0.01). Functional experiments revealed that APEX1 knockdown led to a reduction in AML cell proliferation. These findings indicated that APEX1 polymorphisms were a potential risk factor for AML and highlighted the important role of APEX1 in regulating AML cell differentiation and proliferation.

Maternal illnesses during pregnancy and the risk of childhood cancer: A medical-record based analysis (UKCCS).

Often relying on mother's recollections of past events, the possible relationship between maternal illness in pregnancy and risk of malignancy in their offspring has long been a focus of research. Free from recall bias, this study of childhood cancer (0-14 years) examined these associations using data abstracted from mothers' primary-care (1623 cases, 2521 controls) and obstetric (2721 cases, 5169 controls) records. Maternal infections and other illnesses in pregnancy were examined for any possible associations with childhood leukaemia, lymphoma, CNS or embryonal tumours using pooled information from the two medical record sources (2885 cases and 5499 controls), accounting for potential confounders. Maternal anaemia was associated with childhood acute myeloid leukaemia (AML) (odds ratio, OR = 2.07, 95%CI [1.40-3.08]). Anaemia during pregnancy was also recorded more frequently in the notes of mothers of children with medulloblastoma, retinoblastoma and embryonal rhabdomyosarcoma: ORs 2.36 [1.36-4.11], 1.83 [1.01-3.33] and 2.91 [1.64-5.16] respectively. Other associations included urinary tract infections (UTIs) and non-Hodgkin lymphoma (NHL); preeclampsia and NHL; and polyhydramnios with both AML and NHL. No evidence was found to suggest that influenza during pregnancy impacted on childhood leukaemia risk. In conclusion, our findings are supportive of an association between maternal anaemia in pregnancy and childhood AML, and maternal anaemia and embryonal tumours; underscoring the need for further research exploring the potential causes and roles of iron and vitamin deficiencies. Due to small numbers and lack of corroborative evidence, the associations observed for UTIs, preeclampsia, and polyhydramnios must be treated cautiously.

Abstract 4132120: Down syndrome-trisomy-mediated gene, Dscr-1, protects against lifestyle-related vascular diseases

Epidemiological studies indicate that individuals with Down syndrome (DS) have an increased risk of leukemia and neuronal diseases but a significantly reduced incidence of most solid tumors and advanced vascular dysfunction. This suggests that one or a combination of trisomy genes on human chromosome 21 (HSA21) or murine chromosome 16 ( Mmu16 ) may be responsible for protecting against vasculopathy. Our previous research has shown that the Down syndrome critical region (Dscr)-1 gene, located on HSA21 or Mmu16 , encodes a feedback modulator of calcineurin-NFAT signaling in endothelial cells (ECs). Null mutation or overexpression of Dscr-1 has been found to increase or prevent septic mortality, angiogenesis, liver steatosis, and susceptibility of tumor metastasizing to the lung, respectively, demonstrating its significant role in these processes. In a unique approach, we crossed DS model mice with ApoE -null mice and fed them a high-fat diet (HFD) for 12 weeks to survey the effects of DS-related genes on atherosclerosis. The results were striking, with HFD-mediated increased LDL and triglyceride levels in ApoE -null mice significantly reduced in the combined DS plus ApoE -null mice. This innovative method allowed us to observe a remarkable (~35%) reduction in ApoE-null mediated atheroma formation in the DS model. This finding was also replicated in EC-specific DSCR-1 transgenic (DSCR-1 ECTg ) mice. Furthermore, to test the effect of HSA21, we have collected DS patient-derived trisomy and disomy iPS cells and executed them for the chromatin conformation capture analysis and the in vitro ECs differentiation experiments. DS-derived trisomy iPS cells already changed the whole chromatin structure, typically within the X chromosome. Moreover, the trisomy iPS-derived ECs revealed less proliferation compared to the disomy. RNA-seqs indicated trisomy iPS derived ECs dramatically (21-fold) increased DSCR-1 , but some HSA21 genes, Alzheimer’s related App and Bace2 , e.g., were inversely reduced the expression. Our comprehensive studies not only shed new light on the mechanisms of atherosclerosis in vascular pathology but also offer potential therapeutic strategies. The discovery of the Dscr-1 gene on the DS chromosome, which could be a powerful tool in combating lifestyle-related vascular diseases, underscores the significance of our research.

Clinical Risk Factors for High-Dose Methotrexate-Induced Oral Mucositis Following Individualized Dosing.

Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels. This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis. The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis. Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis.

Residential exposure to solar ultraviolet radiation and risk of childhood hematological malignancies in Switzerland: A census-based cohort study.

Still little is known about possible environmental risk factors of childhood hematological malignancies (CHM). Previous studies suggest that ultraviolet radiation (UVR) exposure is associated with a lower risk of acute lymphoblastic leukemia (ALL) in children. We investigated the association between solar UVR exposure and risk of CHM in Switzerland, a country with greatly varying topography and weather conditions. We included all resident children aged 0-15 years from the Swiss National Cohort during 1990-2016 and identified incident cancer cases through probabilistic record linkage with the Swiss Childhood Cancer Registry. We estimated the overall annual mean UV level and the mean level for the month of July during 2004-2018 at children's homes using a climatological model of the midday (11 am-3 pm) UV-index (UVI) with a spatial resolution of 1.5-2 km. Using risk-set sampling, we obtained a nested case-control data set matched by birth year and fitted conditional logistic regression models (virtually equivalent to analyzing full cohort data using proportional hazards models) adjusting for sex, neighborhood socio-economic position, urbanization, air pollution, and background ionizing radiation. Our analyses included 1446 cases of CHM. Estimated adjusted hazard ratios (HR) per unit increase in UVI in July were 0.76 (95% CI 0.59-0.98) for leukemia and 0.74 (0.55-0.98) for ALL. Results for annual exposure were similar but confidence intervals were wider and included one. We found no evidence for an association for lymphoma overall (HR 1.14, 95% CI 0.59-2.19 for annual exposure) or diagnostic subgroups. Our study provides further support for an inverse association between exposure to ambient solar UVR and childhood ALL.

Infections Deaths in Acute Lymphoblastic Leukemia More Frequent in High Risk Leukemia

Abstract Background Acute lymphoblastic leukemia (ALL) in children currently has more than 90% survival in higher resource countries. However, in less resource countries, the survival rates are lower and infections are frequent causes. Risks for infections and poor outcomes vary during the chemotherapy phases. There is a paucity of data concerning the frequencies of the chemotherapy phase where the event is more probable. Our primary objective is to describe infections frequencies and outcomes of infection in children and also to look for association with risk factors. Methods Patients (Pts) were treated according to ALLIC-BFM-2010 protocol, a simpler branch of the BFM-AEIOP protocol and accrued prospectively. The main question is comparing outcomes of two randomizations using higher dose chemotherapy based on the leukemia risk. The risk severity was based on levels of measurable residual disease (&amp;lt;0.1, 0.1-10, &amp;gt;10 %,) and categorized in high (HR), intermediate (IR), and low (LR) risks. In SR Pts with B-cell-precursor ALL two doses of daunorubicin were prescribed in induction compared with four doses in all others. In consolidation, high-dose methotrexate was administered at 5g/m2 for SR/IR T-cell ALL and at 2g/m2 for SR/IR B-precursor-ALL. Consolidation for HR pts consisted of three intensive polychemotherapy blocks. Only T-ALL and HR pts age &amp;gt; 1 year received prophylactic cranial radiotherapy (12 Gy). Therapeutic cranial radiotherapy was reserved for pts with initial CNS. We performed a descriptive analysis, comparison of frequencies and proportions using Fisher test/Ji2. For time to event proportion we used Cox Analysis. Results 2232 de novo ALL pts were analyzed. Median age 5y (IQR 3-10), 56.3% were males. 2.1% had Down Syndrome; 24% categorized as HR, 56% as IR, and 20% as LR. The Immunophenotype analysis mostly B lineage (88.8%) and less T lineage (11.2%). The majority (96.7%) of pts achieved complete remission. Estimated mean time of survival was 8.8 years (ES 0.099, CI 95% 8.38-8.77) and the overall survival rate was 74 % (0.01). Trial wide, 518 (23.2%) pts died, 59 (2.6%) pts had criteria for clinical sepsis and 459 (20%) for not related sepsis causes. According to phase of the protocol, in less than one month from diagnosis, 21 events (35.6%) were observed; from 2-3 months 9 events (15.3%), from 4-6 months 6 events, (10.2%) and afterwards 23 events (39%) (p-value 0.000). No difference was found on T vs B immunophenotype, sex, age or Down syndrome. (P-value NS). However significant differences were found on risk groups 26/538 pts (4.8%) died on HR, 24/1248 (1.9%) in IR and 9/433 (2.1%) on standard risk (p-value 0.009). There was an association between the rates of sepsis and death on pts randomized to I and II protocols (p-value 0.007 and P-value 0.007). Conclusion In this large cohort of pts, we could demonstrate association between sepsis and mortality in those high-risk groups and in those pts randomized to higher chemotherapy doses. These results will allow to establish strategies to prevent infections or maximize medical interventions preventing poor infectious outcomes in high-risk groups.

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML

AbstractMeasurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.

Alpha-1 antitrypsin deficiency associated with increased risks of skin cancer, leukemia, and hepatic cancer: A nationwide cohort study.

α1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population. In a nationwide nested study, we identified 2702 individuals with α1-antitrypsin deficiency and 26,750 control subjects without α1-antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years. Individuals with α1-antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1-antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1-antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13). Individuals with α1-antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population.

Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review.

The preventability of acute lymphocytic leukemia during childhood is currently receiving great attention, as it is one of the most common cancers in children. Among the known risk factors so far are those affecting the development of gut microbiota, such as a short duration or absence of breastfeeding, cesarean section, a diet lacking in short-chain fatty acids (SCFAs), the use of antibiotics, absence of infection during infancy, and lack of pets, among other factors. Namely, it has been shown that iron deficiency anemia (IDA) and lack of vitamin D may cause intestinal dysbiosis, while at the same time, both increase the risk of hematological malignancies. The presence of IDA and vitamin D deficiency have been shown to lead to a decreased proportion of Firmicutes in stool, which could, as a consequence, lead to a deficit of butyrate. Moreover, children with IDA have increased blood concentrations of cadmium, which induces systemic inflammation and is linked to the onset of an inflammatory microenvironment in the bone marrow. Finally, IDA and Cd exposure increase fibroblast growth factor 23 (FGF23) blood levels, which in turn suppresses vitamin D synthesis. A lack of vitamin D has been associated with a higher risk of ALL onset. In brief, as presented in this review, there are three independent ways in which IDA increases the risk of acute lymphocytic leukemia (ALL) appearance. These are: intestinal dysbiosis, disruption of vitamin D synthesis, and an increased Cd load, which has been linked to systemic inflammation. All of the aforementioned factors could generate the appearance of a second mutation, such as ETV6/RUNX1 (TEL-AML), leading to mutation homozygosity and the onset of disease. ALL has been observed in both IDA and thalassemia. However, as IDA is the most common type of anemia and the majority of published data pertains to it, we will focus on IDA in this review.

Abstract A079: The impact of Indigenous American ancestry on the risk of acute lymphoblastic leukemia and the implications for future study designs

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino (H/L) children having up to 1.4 times the rate of ALL compared to their non-Hispanic White counterparts. This disparity has not been fully explained by environmental factors, suggesting the role of understudied genetic variants, particularly ones found in Indigenous American (IA) ancestry inherited by Latinos. In this study, we characterized the impact of IA ancestry on the frequency and effect size of known ALL risk alleles. We found that elevated risk of ALL in Latinos may be conferred by increased frequency of risk alleles due to IA ancestry. For instance, in an analysis of Latinos from the California Cancer Linkage Project (CCRLP; 1,930 cases, 2,103 controls) and the California Childhood Leukemia Study (CCLS; N = 605 cases, 515 controls), we found that, across independent known ALL loci (N=21), more loci than expected by chance showed a significant association between IA ancestry and increasing risk (p = 0.015). Compared to randomly-sampled, frequency-matched alleles from the genome, the risk alleles at all known ALL loci also showed a significant association with IA ancestry (46.9 % for known risk alleles vs. 43.5 % for matched alleles; ). The IA haplotype had 1.39 times the odds (95% CI: 1.35 – 1.43; ) of harboring the risk allele compared to the non-IA haplotype. Conversely, in a combined Latino sample of 2,535 cases and 9,035 controls, we found no evidence of GxAncestry interaction on ALL risk across all known loci (min P = 0.0026, prior to adjusting for multiple testing), suggesting that ALL risk alleles do not have increased effects on the IA ancestry background. This lack of synergism between local ancestry and genotype in ALL has methodological implications for gene discovery in admixed populations. To explore this, we implemented Tractor, a method that models genotype effects by ancestry, and thus is best powered in the presence of effect size heterogeneity by ancestry. Across known loci, we found that Tractor had 36.1% decreased power compared to standard GWAS. Taken together, our results suggest that the disproportionate burden of ALL in Latino populations may arise from the enrichment of risk alleles within the IA ancestry component, possibly driven by immunity- related selective pressures. Finally, future genetic studies of ALL in Latino patients may benefit from methods that incorporate contributions from ancestry to increase the statistical power in identifying associations, rather than leverage effect size heterogeneity across ancestries. Citation Format: Jalen Langie, Libby Morimoto, Xiaomei Ma, Catherine Metayer, Joseph L. Wiemels, Adam J. de Smith, Charleston W.K. Chiang. The impact of Indigenous American ancestry on the risk of acute lymphoblastic leukemia and the implications for future study designs [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A079.

Abstract A032: Disparities in molecular subtypes of acute lymphoblastic leukemia incidence by age, race/ethnicity, and sex in the United States

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children and a heterogeneous disease comprising several molecular subtypes. The increased risks of ALL in individuals assigned male at birth and in those of Hispanic/Latino ethnicity compared to non-Hispanic White individuals are well known. Less well-established are potential differences in the prevalence of specific molecular subtypes of ALL by sex or racial/ethnic groups. Here, we provide updates on incidence patterns for lymphoid leukemias reported by cancer registries across the United States, leveraging recent data on molecular subtypes of ALL. We obtained data from the North American Association of Central Cancer Registry (NAACCR) for United States-specific incidence cases from 2000 through 2020. Diagnoses and leukemia subtype reporting, limited to ALL only, was based on the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). Age-adjusted (2000 US Standard) incidence rates (AAIR) were calculated using SEER*Stat (version 8.4.3). Incidence rate ratios (IRR) were calculated to assess patterns in leukemia incidence by sex and by race/ethnicity across three age groups: 0- 14 (children), 15-39 (adolescents and young adults, AYA) and 40+ (older adults) years. Information on selected molecular subtypes of ALL was available for cases diagnoses 2010 onwards, from ICD-0-3 histology codes that were determined by genetics and/or immunophenotyping. Overall and in each age group compared to non-Hispanic Whites (NHWs), Blacks/African- Americans (B/AAs) had significantly lower AAIRs for ALL whereas Hispanic/Latinos (H/Ls) had significantly higher AAIRs, in particular for B-cell ALL. Analysis by molecular subtypes revealed that overall, H/Ls were at higher risk for BCR::ABL1 translocation than NHWs, with the greatest difference seen in AYAs in which H/Ls had a 2.5-fold (95% CI=2.08-3.00) higher risk of BCR::ABL1. In children, H/Ls had significantly higher incidences of several ALL subtypes compared with NHWs, including BCR::ABL1 (IRR=1.5; 95% CI=1.13-1.98) and TCF3::PBX1 (IRR=2.0; 95% CI=1.43-2.79) but also ETV6::RUNX1 and high hyperdiploidy (both IRR=1.27; 95% CI=1.12-1.43). Males were at significantly higher risk than females for ALL and its subtypes across all ages combined and stratified age categories. In particular, males had a 2.5- fold increased risk of precursor T-cell lymphoblastic leukemia compared to females (IRR=2.5; 95% CI=2.28-2.73) in all ages combined, and a 3.0-fold increased risk in both AYAs (95% CI=2.59-3.46) and older adults (95% CI=2.54-3.54). Among molecular subtypes, the highest IRR was observed for BCR::ABL1 in AYAs wherein males were at 50% increased risk (IRR=1.5; 95% CI=1.27-1.76). In addition to confirming the previously reported disparities in ALL incidence by race/ethnicity and by sex, we report an increased incidence of particular molecular subtypes of ALL in Hispanics/Latinos and in males. Studies to investigate potential genetic and environmental risk factors underlying these disparities are warranted. Citation Format: Anmol A. Pardeshi, Juanita Elizabeth Quino, Nicholas Acuna, Talar Habeshian, Raymond Hughley, Isabella Ortiz, Michelle Tran, Ying Yan, Cindy Zamora, Joseph l. Wiemels, Kai-Ya Tsai, Lihua Liu, Adam J de Smith. Disparities in molecular subtypes of acute lymphoblastic leukemia incidence by age, race/ethnicity, and sex in the United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A032.

Glutamine metabolism-related genes predict the prognostic risk of acute myeloid leukemia and stratify patients by subtype analysis

BackgroundAcute myeloid leukemia (AML) is a genetically heterogeneous disease in which glutamine (Gln) contributes to AML progression. Therefore, this study aimed to identify potential prognostic biomarkers for AML based on Gln metabolism-related genes.MethodsGln-related genes that were differentially expressed between Cancer Genome Atlas-based AML and normal samples were analyzed using the limma package. Univariate, least absolute shrinkage, selection operators, and stepwise Cox regression analyses were used to identify prognostic signatures. Risk score-based prognostic and nomogram models were constructed to predict the prognostic risk of AML. Subsequently, consistent cluster analysis was performed to stratify patients into different subtypes, and subtype-related module genes were screened using weighted gene co-expression network analysis.ResultsThrough a series of regression analyses, HGF, ANGPTL3, MB, F2, CALR, EIF4EBP1, EPHX1, and PDHA1 were identified as potential prognostic biomarkers of AML. Prognostic and nomogram models constructed based on these genes could significantly differentiate between high- and low-risk AML with high predictive accuracy. The eight-signature also stratified patients with AML into two subtypes, among which Cluster 2 was prone to a high risk of AML prognosis. These two clusters exhibited different immune profiles. Of the subtype-related module genes, the HOXA and HOXB family genes may be genetic features of AML subtypes.ConclusionEight Gln metabolism-related genes were identified as potential biomarkers of AML to predict prognostic risk. The molecular subtypes clustered by these genes enabled prognostic risk stratification.

UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease

AbstractHematopoietic stem cell (HSC) transplantation with lentiviral vector (LVV)-transduced autologous cells has proven an effective therapeutic strategy for sickle cell disease (SCD). However, ex vivo culture or proliferative stress associated with in vivo reconstitution may amplify any underlying genetic risk of leukemia. We aimed to minimize culture-induced stress and reduce genomic damage during ex vivo culture and enhance stem cell fitness and reconstitution of SCD CD34+ cells transduced with BCL11A shmiR-encoding LVV. UM171, a pyrimidoindole derivative, can expand normal HSCs during in vitro culture and has been shown to be safe and effective using umbilical cord blood. We examined the effect of UM171 during ex vivo LVV transduction of SCD HSCs. Culture of SCD CD34+ HSCs with UM171 during transduction reduced DNA damage and reactive oxygen species, decreased apoptosis, and was associated with increased numbers of immunophenotypically defined long-term HSCs. UM171 increased the engraftment of LVV-transduced human HSCs in immunodeficient mice and barcode tracing revealed increased clonal diversity of engrafting cells. In competitive transplantation assays, analysis of bone marrow showed that cells transduced in the presence of UM171 consistently outcompeted those transduced under control conditions. In summary, exposure of SCD peripheral blood CD34+ cells to UM171 during LVV transduction enhances stem cell fitness. These findings suggest manufacturing of genetically modified HSCs in the presence of UM171 may improve efficacy, safety, and sustainability of gene therapy using ex vivo approaches. BCL11A shmiR-encoding LVV is in clinical trials to treat SCD (NCT03282656), UM171 is in clinical trials to culture umbilical cord blood (NCT02668315).

Structural and functional alterations in hematological parameters among individuals at clinically high risk for acute lymphocytic leukemia

Abstract: Acute lymphocytic leukemia (ALL) is a diverse category of hematological malignancies defined by the clonal proliferation of immature lymphoid cells. While advances in diagnostic procedures and treatment modalities have improved results for many patients, a group of them exhibit clinical characteristics that indicate a high risk of disease progression and unfavorable consequences. Understanding the underlying molecular processes and developing accurate prognostic indicators in this high-risk group is critical for personalized treatment approaches and better patient outcomes. Hematological markers, immunophenotyping profiles, and chromosomal defects in people who were clinically high risk (CHR) for ALL are discussed in this review. Alterations in hematological markers, such as elevated white blood cell counts, decreased hemoglobin levels, and thrombocytopenia, are indicative of the aggressive nature of high-risk ALL. Immunophenotyping investigations revealed abnormal expression patterns of lineage-specific markers, indicating clonal proliferation and differentiation arrest. Furthermore, cytogenetic examination revealed frequent chromosomal defects, such as the Philadelphia chromosome and hyperdiploidy, which have been linked to a poor prognosis in ALL patients. The combination of hematological, immunophenotypic, and cytogenetic data gives a thorough knowledge of disease biology and assists in risk assessment for patients with CHR for ALL. The present review elucidates the intricate interaction of hematological, immunophenotypic, and cytogenetic abnormalities in persons at clinically high risk for ALL, emphasizing the importance of integrated diagnostic techniques to enhance patient outcomes and optimize treatment strategies.

Domestic radon exposure and childhood cancer risk by site and sex in 727 counties in the United States, 2001–2018

BackgroundChildhood cancer has few established risk factors and environmental influences are underexplored. This ecologic study investigated the association between domestic radon exposure and childhood cancer risk in a large sample of United States (U.S.) counties. MethodsMonthly ZIP code-level basement radon estimates from a geographic machine learning model were aggregated annually to counties, analyzed as continuous and dichotomized (cut point: 74 Bq/cubic meter (Bq/m3) or 2.0 picocuries/L (pCi/L)) versions, and lagged by one year. Annual county-level counts of sex- and site-specific (all, leukemia, brain and central nervous system [CNS], and other sites) incident cancer diagnoses among those 0–19 years from 2001 to 2018 were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database. Sex- and site-specific counts were modeled as zero-inflated Poisson distributions in a Bayesian spatiotemporal framework and sequentially adjusted for random and fixed confounder effects. ResultsIn 727 counties across 14 states, the average population aged 0–19 years was 41,599 people at baseline. Results from fully adjusted spatiotemporal statistical models indicated 1.05 (95% credible interval, CrI: 1.00, 1.09) times higher relative risks (RRs) of leukemia among both sexes and a RR of 1.06 (95%CrI: 1.00, 1.12) in males from a 50 Bq/m3 (1.35 pCi/L) increase in radon concentration the year prior. For radon exposures ≥74 Bq/m3 (2.00 pCi/L) the year prior, RRs were 1.08 (95%CrI: 1.02, 1.15) for both sexes and 1.12 (95%CrI: 1.04, 1.22) for females. No associations were found with other cancer sites or sexes from prior year radon exposures. ConclusionsCounty-level childhood leukemia risk in both sexes were associated with average radon levels below U.S. Environmental Protection Agency guidelines recommending mitigation (148 Bq/m3 or 4.00 pCi/L). These findings warrant further investigation using population-based and individual-level study designs.

Large-scale genome-wide association studies reveal the genetic causal etiology between ankylosing spondylitis and risk of leukemia and lymphocytic malignancies.

Evidence from multiple observational studies suggests that ankylosing spondylitis (AS) is associated with leukemia and lymphocytic malignancies. However, the obtained results are inconsistent, and the causal relationship still needs to be determined. In this context, we utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between AS and leukemia and lymphocytic malignancies. The analysis was conducted through published genome-wide association studies (GWAS). We obtained genetic data on AS as the exposure and leukemia, including lymphocytic leukemia, myeloid leukemia, and lymphocytic malignancies including lymphoma, multiple myeloma (MM) as the endpoint. The main method to evaluate causality in this analysis was the inverse variance weighting (IVW) technique. Additionally, we employed the weighted mode, weighted median, and MR-Egger regression for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multi-effect analyses are carried out. In a random-effects IVW analysis, we found that genetic susceptibility to AS was associated with an increased risk of leukemia (OR = 1.002; 95%CI, 1.001-1.003; p = 0.003) and an increased risk of lymphocytic leukemia [OR = 1.001; 95% CI, (1.000-1.002), p = 0.008]. There was no evidence that AS was associated with lymphoma, myeloid leukemia, and MM. Our research indicates that AS was associated with an elevated risk of leukemia, and further analysis of specific types of leukemia showed that the risk of lymphocytic leukemia was associated with AS. Our findings highlight the importance of active intervention and monitoring to mitigate leukemia, especially lymphocytic leukemia risk in patients with AS.

Associations of polymorphisms of glutathione-S-transferase and N-acetyltransferase 2 genes in children with acute lymphoblastic leukemia

The development of personalized medicine is inextricably linked with the study of the patient’s genetic profile, which determines not only the features of the course of the disease, but also the risks of its occurrence. Purpose. The aim of the work was to study possible associations between the genetic polymorphisms GSTT1, GSTM1, NAT2 and predisposition to the development of acute lymphoblastic leukemia in children of the East Siberian region. Material and methods. A total of 82 children with acute lymphoblastic leukemia and 227 healthy volunteers with no history of hematological pathology were examined. Deletion polymorphisms in the glutathione S-transferase GSTT1 and GSTM1 genes were detected by polymerase chain reaction (PCR) with electrophoretic detection of amplification products in agarose gel; the type of acetylation was determined by genotyping SNP rs1495741 of the NAT2 gene by conducting a polymerase chain reaction in real time. The material for the study was DNA samples isolated from buccal epithelium samples. Results. Statistical processing allowed us to draw the following conclusions: the rate of acetylation of xenobiotics does not affect the risk of acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. Conclusion. There is no associative relationship between deletions in the GSTM1 and GSTT1 genes and the risk of developing acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. It was found that the risk of developing acute lymphoblastic leukemia in children was significantly higher with the variant of combinations of alleles of the rapid type of NAT2 acetylation and normal activity of GSST1 and GSTM1 (G/G, active, active).

Global, regional, and national burdens of leukemia from 1990 to 2019: A systematic analysis of the global burden of disease in 2019 based on the APC model.

Leukemia is the tenth most common cause of cancer death worldwide and one of the most important causes of disability. To understand the current status and changing trends of the disease burden of leukemia at the global, regional, and national levels, and to provide a scientific basis for the development of leukemia prevention and treatment strategies. Based on open data from the Global Burden of Disease Study 2019 (GBD 2019), R software was used to calculate estimated annual percentage changes to estimate trends in the age-standardized incidence (ASIR) and the age-standardized disability-adjusted life years (DALY) rate due to leukemia and its major subtypes from 1990 to 2019. In 2019, globally, the number of incidences and DALYs of leukemia were 643.6 × 103 (587.0 × 103, 699.7 × 103) and 11,657.5 × 103 (10529.1 × 103, 12700.7 × 103), respectively. The ASIR (estimated annual percentage change (EAPC) = -0.37, 95%UI -0.46 to -0.28) and the age-standardized DALY rate (EAPC = -1.72, 95%UI -1.80 to -1.65) of leukemia showed a decreasing trend from 1990 to 2019. The APC model analysis showed that the age effect of leukemia risk was a "U"-shaped distribution of relative risk (RR) with increasing age from 1990 to 2019, globally. The time effect was an increase in incidence rate with increasing years but a decrease in DALY rate with increasing years. The cohort effects of both incidence and DALY rates tended to increase and then decrease with the development of the birth cohort. In 1990 and 2019, smoking, high body-mass index, occupational exposure to benzene, and occupational exposure to formaldehyde were risk factors for DALY in leukemia, especially in areas with high SDI. From 1990 to 2019, the disease burden of leukemia showed a decreasing trend, but it is worth noting that its overall severity is still very high. The disease burden of leukemia varies greatly from region to region, and exclusive strategies for the prevention and treatment of leukemia should be developed according to the economic and cultural development of each region.

Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia

BackgroundClinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear. MethodsThis work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes. ResultsCombining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70–3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06–3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88–3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %. ConclusionOur study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

Wood dust and risk of leukemia: Systematic review and meta-analysis.

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. 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. 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. 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.