AbstractAcute Leukemia Research Articles

Epidemiology of childhood acute leukemias

Abstract Acute leukemias are the largest group of childhood cancers. According to the latest WHO data 80,491 leukemias were diagnosed in 2020 alone. In the coming years the incidence worldwide will continue at a similar level. The morbidity correlates with biological determinants such age, gender and race. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Both the incidence and curability are also influenced by age, gender, and race. The peak of incidence of leukemia occurs between the ages of 1–4 years and 9–19. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Boys suffer from leukemia more often than girls. In 2020 58.2% of diagnoses were for boys. Numerous factors contribute to the development of acute leukemia. In the case of young children, a notable association exists between acute leukemia and infections caused by viruses such as EBV or HHV-6. Furthermore, the risk of leukemia can be elevated by allergies, which involve Th1/Th2 lymphocyte-dependent mechanisms. A familial predisposition to tumorigenesis in children is observed in Li-Fraumeni Syndrome. Also, genetic diseases such as Down syndrome and Fanconi anemia are associated with an increased risk of acute leukemia. Previous exposure to radiation therapy or the use of anti-cancer drugs can also lead to the development of secondary cancers, including leukemia. The analysis of risk factors can be used to support efforts aimed to reduce potentially harmful exposure and to decrease the risk of disease.

Prognostic significance of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in association with clinical parameters in acute leukemia patients

Acute leukemia (AL) is a haematological neoplasm associated with undifferentiated clonal expansion resulting in impaired haematopoiesis and bone marrow failure. Neutrophils, platelets and lymphocyte cells have been involved in inflammation and peripheral neutrophil-to-lymphocyte (NLR) and platelet-tolymphocyte (PLR) ratios play a vital role in the prognosis of the disease. To study the association of NLR and PLR in the clinical parameters of acute leukemia patients, a study of 42 clinically diagnosed AL patients was conducted in our institute. The patients were categorized into two groups based on cut off points of NLR=2.8 and PLR=174. The haematological parameters like gender (p= 0.0074), bilirubin direct (p=0.0429), bilirubin total (p=0.0396) had a significant difference in NLR and haemoglobin (p=0.0316), platelet count (p=0.0140) were having a significant difference in PLR. There was a significant difference among the flowing parameters like TLC (p=0.0229), Platelet counts (p=0.0006) with PLR. Absolute lymphocyte count (ALC) was negatively correlated with both NLR and PLR having a significant difference (p=0.0495) and (p=0.0360) respectively. A negative correlation was observed in absolute neutrophil count (ANC) having a significant difference (p= 0.0456). The baseline characteristics of NLR and PLR are significantly associated with disease-specific and overall survival in acute leukemia could potentially be helpful in routine clinical practice and future clinical trials to identify patients.

Cell surface expression of GRP78 and CXCR4 is associated with childhood high-risk acute lymphoblastic leukemia at diagnostics

Acute lymphocytic leukemia is the most common type of cancer in pediatric individuals. Glucose regulated protein (GRP78) is an endoplasmic reticulum chaperone that facilitates the folding and assembly of proteins and regulates the unfolded protein response pathway. GRP78 has a role in survival of cancer and metastasis and cell-surface associated GRP78 (sGRP78) is expressed on cancer cells but not in normal cells. Here, we explored the presence of sGRP78 in pediatric B-ALL at diagnosis and investigated the correlation with bona fide markers of leukemia. By using a combination of flow cytometry and high multidimensional analysis, we found a distinctive cluster containing high levels of sGRP78, CD10, CD19, and CXCR4 in bone marrow samples obtained from High-risk leukemia patients, which was absent in the compartment of Standard-risk leukemia. We confirmed that sGRP78+CXCR4+ blood-derived cells were more frequent in High-risk leukemia patients. Finally, we analyzed the dissemination capacity of sGRP78 leukemia cells in a model of xenotransplantation. sGRP78+ cells emigrated to the bone marrow and lymph nodes, maintaining the expression of CXCR4. Testing the presence of sGRP78 and CXCR4 together with conventional markers may help to achieve a better categorization of High and Standard-risk pediatric leukemia at diagnosis.

Genetic and immunophenotypic diversity of acute leukemias in children

Abstract Acute leukemias are the most commonly diagnosed malignancies in children. Acute leukemias constitute a heterogeneous group of cancers resulting from clonal outgrowth and accumulation of immature precursor cells of different hematologic lineages. Cancerous transformation begins with disruption of cell maturation mechanisms triggered by particular environmental or endogenic factors, including innate and acquired immunodeficiencies as well as autoimmune diseases. Research in the field of acute leukemias has revealed many possible genetic abnormalities in leukemic cells, including both structural and numerical aberrations. The former can produce some particular fusion genes, yielding fusion protein products which can have an oncogenic potential in hematopoietic cells. Some of them, including translocations resulting in fusion product formation BCR-ABL1 and different fusion products involving the KMT2A gene, are markers of adverse prognosis, whereas numerical aberrations with high hyperdiploidy and chromosome number exceeding 51 are markers of favorable prognosis. Detection of these aberrations already has a well-grounded clinical significance in acute lymphoblastic leukemia and plays an important role in patient risk stratification. The appearance of particular genetic changes often correlates with the expression of certain markers on the surface of leukemic cells. Determination of expression or lack of specific antigens, that is, immunophenotyping, is possible with the use of the flow cytometry technique. Flow cytometry is currently considered as a fast and broadly available technique which can provide clinically useful information in a relatively short time after biological specimen collection. Flow cytometry also enables appropriate classification of acute leukemias.

Maternal and Fetal Outcomes of Acute Leukemia in Pregnancy: A Retrospective Study of 52 Patients.

Acute leukemia during pregnancy (P-AL) is a rare disease with limited data regarding the management and outcomes of mothers and fetuses. We retrospectively analyzed the characteristics, pregnancy outcomes and maternal and neonatal prognoses of 52 patients with P-AL collected from January 2013 to December 2020 in our center. Seventeen (32.7%) patients received chemotherapy during pregnancy (exposed cohort), while 35 (67.3%) received chemotherapy after abortion/delivery (nonexposed cohort). Twenty-six (50.0%) pregnancies ended with abortion, and 26 (50.0%) babies were born through spontaneous delivery or cesarean section. Seven infants (26.9%) were born in the exposed cohort, while 19 infants (73.1%) were born in the nonexposed cohort. Fetuses in the exposed cohort had lower gestational ages (P=0.030) and birth weights (P=0.049). Considering the safety of the fetus, seven patients in the exposed cohort received low-dose chemotherapy, one patient received all-trans retinoic acid (ATRA) and one patient only received corticosteroids as induction therapy. Patients received low-dose chemotherapy as induction therapy had a lower complete remission (CR) rate (P=0.041), and more patients in this group received HSCT (P=0.010) than patients received intensive chemotherapy. Patients who delayed chemotherapy in the nonexposed cohort experienced a trend toward a higher mortality rate than patients who received timely chemotherapy (P=0.191). The CR (P = 0.488), OS (P=0.655), and DFS (P=0.453) were similar between the exposed and nonexposed cohorts. Overall, the 4-year overall survival (OS) and disease-free survival (DFS) rates were estimated at 49.1% and 57.8%, respectively. All newborns were living, without deformities, or developmental and intellectual disabilities. Our study indicated that P-AL patients in the first trimester might tend to receive chemotherapy after abortion. Both the status of disease and patients’ willingness should be taken into consideration when clinicians were planning treatment strategies in the second or third trimester. Low-dose or delayed chemotherapy might decrease the efficacy of induction therapy and survival rate of patients, but HSCT could improve the prognosis.

The association of complex genetic background with the prognosis of acute leukemia with ambiguous lineage

Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018. The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. Among the patients underwent high-throughput sequencing, 89.5% were detected at least one mutation and the median number of gene mutation was 3 (0–8) per sample. The most frequently mutated genes were NRAS (4, 21%), CEBPA (4, 21%), JAK3 (3, 16%), RUNX1 (3, 16%). The mutations detected in mixed-phenotype acute leukemia (MPAL) enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. The survival analysis strongly suggested that mutation burden may play important roles to predict the clinical outcomes of ALAL. In addition, the patients excluded by WHO criteria had even worse clinical outcome than those included. The association of the genetic complexity of blast cells with the clinical outcomes and rationality of the diagnostic criteria of WHO system need to be evaluated by more large-scale prospective clinical studies.

A Rare Pediatric Case Report With Review of Literature for the Diagnosis of Acute Megakaryoblastic Leukemia (FAB M7)

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) accounting for 3%–10% of primary AML in childhood. Clinical manifestations of AML patients can include low grade of fever, diarrhea, easy bruising, failure to growth, and life-threatening clinical manifestations. Laboratory tests are very crucial to make a definitive diagnosis and treatment. We report here an uncommon case of AMKL in a 12-month-old boy who presented with general paleness and fatigue. Based on blood film investigation, bone marrow examination report, and immunophenotyping, he was diagnosed as a case of AMKL without Down syndrome.

Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.

The diagnostic profile of rare acute myelomegakaryoblastic leukemia

Acute myelomagakaryocytic leukemia is a diagnostic and therapeutic challenge owing to its heterogeneity and overlapping features with other types of acute leukemia. In order to build a diagnostic profile, we analyzed the biological, clinical and hematologic characteristics of acute myelomagakaryocytic leukemia. We found that, in three patients diagnosed with acute myelomagakaryocytic leukemia, there were two types of leukemia cells. One type was myeloblastic with positive peroxidase (POX) stainig and the expression of antigens CD13 and CD33. The other type was megakaryoblastic with negative POX staining and the expression of antigens CD36, CD41, CD42a and CD61. Three patients displayed the same cytogenetic abnormality, a (9: 22) translocation. Among the three patients with RT-PCR, two patients displayed BCR-ABL fusion gene amplification and one patient showed a previously undescribed OTT-MAL fusion gene amplification.

Abstract 801: Acute leukemia excess in families

Abstract Acute leukemia (AL) is the most common type of childhood cancer and has two major subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Historically, studies in this field have pointed out driver somatic mutations with different mechanisms of pathogenesis. Family-based and large-scale high-throughput sequencing studies have recently uncovered several genetic germline variants, indicating an inherited origin. Familial history of cancer (FHC) is associated with an increased risk of both ALL and AML. Herein we explore the excess of hematological malignancies (HM) in first-degree relatives of patients diagnosed under 21 years old and compare rates of FHC between AML and ALL cases. We revisited the registry of the Brazilian group Estudos Multi-Institucionais das Leucemias Infantis (EMiLI) comprised of 89 cancer centers from 2009 to 2019. Socio-demographic, immunomolecular, and self-reported FHC data were collected using a structured questionnaire at the beginning of the follow-up. Descriptive statistics were used to assess the frequency distribution and differences between cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals to evaluate the estimated FHC predisposition to AL. From a total of 5,831 samples, 42.6% were from North/Northeast, 35.7% from South/Southeast, and 21.7% from Midwest macroregions. There was a high frequency of cases (p < 0.001) of Non-White ethnicity in North/Northeast and White ethnicity in South/Southeast. B-cell Precursor ALL was more frequent in Midwest, T-cell acute lymphoblastic leukemia in North/Northeast, and AML cases in South/Southeast. Among 3,618 individuals with AL, 472 had a positive FHC (13%). Of these, 96 (20.3%) reported HM as the origin of cancer. We observed a higher odds of having at least one relative with cancer in AML cases compared to ALL (OR 1.36; 95% CI 1.01-1.82; p = 0.040). When considering only first-degree relatives with any type of cancer, the risk was even more considerable for the AML group than ALL (OR 2.92; 95% CI 1.57-5.42; p = 0.001). With a statistical significance value (p= 0.02), we observed that AML cases present higher odds of having a first-degree relative with FHC with hematologic origin than ALL cases (OR 5.71; 95% CI 1.91-17.08). This effect was not observed analyzing second degree-relatives or relatives with non-hematological malignancies. Our findings suggest that AML is more associated with a positive FHC than ALL, particularly when having a first-degree relative with HM. Both genetic and environmental exposure factors could be involved in the AL subtypes epidemiology. Identifying children with a higher risk of AL would be beneficial by performing early targeted cancer screening and improving prevention and surveillance programs. Further genomic studies exploring Brazilian childhood AL cases with FHC are crucial to elucidate the role of genetic background and ancestry as risk factors associated with leukemogenesis. Citation Format: Daniela P. Mendes-de-Almeida, Francianne G. Andrade, Paulo Chagas-Neto, Maria do Perpétuo Socorro S. Carvalho, José C. Córdoba, Marcelo dos S. Souza, Logan G. Spector, Maria S. Pombo-de-Oliveira, Brazilian Collaborative Study of Childhood Leukemia, Acronym EMiLI. Acute leukemia excess in families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 801.

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia.

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell- and T cell-dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1-refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659.

Acute leukemia and stem cell transplantation

Acute leukemias are a type of clonal proliferative malignancies that affect all ages with a predominance of ALL in children and AML in adults. Left untreated they are lethal and require rapid medical management. Not only it imposes high health risks through complications such as infections, but the treatment itself is also a source of potential risks. Acute leukemias require intense medical observation and care. Current treatment consists of a combination of chemotherapeutic agents, stem cell transplantation and supportive care. Recent research offers a better understanding of the pathogenesis of these diseases and provide an advancement in the field of targeted therapeutic agents.

Chemotherapeutics for Acute Erythroid Leukemia: Research, Present and Future.

Acute erythroid leukemia (AEL) is a subtype of acute myeloid leukemia (AML) with features such as accumulation of maturation-arrested erythroblasts. Compared with AML, the progression of AEL is faster and the prognosis to available therapy is worse. However, its categorization is still being updated and the pathophysiology of AEL is still under research, making diagnosis and chemotherapy challenging for physicians. To achieve better outcomes, therapies should be optimized and new drugs should be developed. In this review, we summarize current strategies of diagnosis and therapies of AEL, and discuss prospective targets for chemotherapeutic agents based on the biological characteristics of AEL neoplastic cells as well as transcriptional factors and pathways related to erythroid differentiation.

Evaluation of the clinical significance of RNase III enzyme DROSHA in pediatrics acute lymphocytic leukemia.

Acute lymphocytic leukemia (ALL) is one of the subtypes of leukemia; it is one of the leading causes of malignancy and morbidity and childhood mortality. This study examined the dysregulation of DROSHA and its clinical implications in ALL. In the case-control investigation, we have included 140 samples, consisting of 70 peripheral whole blood samples diagnosed with ALL and 70 age and sex-matched healthy children, to assess the level of expression of DROSHA mRNA between two groups. Quantitative Real-Time PCR was used to establish the level of DROSHA gene expression in the patients and controls. The results revealed that DROSHA was overexpressed in patients compared with controls (p < 0.001). There were no major differences between DROSHA expression and demographic factors and clinicopathological parameters (p > 0.001). The finding of the study revealed that DROSHA expression in ALL patients is significantly up-regulated; which is suggesting that may be served as a critical role in the pathogenesis of ALL. Also, DROSHA will possibly be utilized as a novel therapeutic target for ALL patients within the future.

Screening for pre-leukemia TEL-AML1 chromosomal translocation in banked cord blood units: cord blood bank perspective.

Acute lymphocytic leukemia is the most common leukemia in children. Many studies suggest the existence of two subsequent hits in order for the disease to occur. TEL-AML1 (ETV6-RUNX1) is considered an initial genetic hit that occurs prenatally and generates a pre-leukemia clone. In cord blood (CB) stem cell transplantation, donor cell leukemia (DCL) is one of the complications associated with the presence of the pre-leukemic clone. The aim of this study was to identify the prevalence of ETV6-RUNX1 translocation in CB units and the feasibility in implementing such a screening test, to ensure the safety of the CB units. A total of 424 CB samples were tested from the CB units banked at KAIMRC-CBB. RNA was extracted and cDNA synthesis was performed on 1ug input RNA using Reverse Transcriptase RT-PCR methodology. Chromosomal translocation ETV6-RUNX1 was tested using real time quantitative PCR methodology. Our study showed undetectable levels of ETV6-RUNX1 in all tested CB samples. The samples were analyzed for the chromosomal translocation ETV6-RUNX1 under controlled conditions, using control and fusion genes with known concentrations. The result of this study does not rule out the importance of this screening test in predicting and/or preventing DCL. Moreover, the outcome strengthens the adopted system in our CBB for mother medical history screening prior to donation. We propose adding this test during the verification testing stage, prior to the release of CB units selected for transplantation rather than at the banking stage.

Acute lymphoid leukemia (LLA): A pediatric case report in dizygotic twins

Acute leukemias are considered neoplasias that reach the hematopoietic system, resulting in rapid clonal expansion and accelerated proliferation of blood cells. In this way, the cells lose their capacity for maturation and differentiation, accumulating young cells (blasts) and without function in the bone marrow. Acute lymphocytic leukemia (ALL) is a neoplasm that affects cells of the lymphoid lineage, but its prevalence occurs in B-cell precursors compared to T cells. It is common to occur in children between 1 and 5 years of age, comprising about 80% of the cases of all leukemias in this age group, but in adults, the probability of being present is lower. The present study aimed at the accomplishment of a case report on acute lymphoid leukemia in children, based on the comparison of risk factors in the family, and the evaluation of socioeconomic interference in the treatment, where, through an explanatory booklet, health professionals and the community about the major signs and symptoms of ALL in children. The research was submitted to the Ethics Committee of the Catholic University Center of Quixadá, through the Brazil Platform where it was analyzed and approved (01673218.2.0000.5046). In this study, we reported the case of two twin sisters who entered the Hospital São Sebastião de Pedra Branca, Ceará at different times, where one was admitted with fever and boulders, and another presenting only fever, after laboratory tests they were referred to a referral hospital in Fortaleza, Ceará, and were then diagnosed with acute lymphoid leukemia. Due to the poor prognosis of this pathology and a possible worsening of the patients' clinical status, they were referred for bone marrow transplantation. Fortunately, after the treatments performed, the twin had a positive evolution, no longer needing to undergo bone marrow transplantation

Health technology assessment-based approach to flow cytometric immunophenotyping of acute leukemias: a literature classification.

Acute leukemia (AL) is a broad, heterogeneous group of malignant diseases. The diagnostic workup of AL is based on several clinical and laboratory findings, including flow cytometric immunophenotyping. However, the role of this assay in the diagnosis of AL has not been systematically investigated. The aim of this study was to determine the accuracy and utility of flow cytometric immunophenotyping in the identification, characterization, and staging of AL. We performed a systematic selection and classification of the literature since 1980, focused on flow cytometric immunophenotyping of AL. We applied a 6-variables model to cover both the technical capabilities and the clinical value of flow cytometric immunophenotyping in the diagnosis of AL. Using 3 key words (acute leukemia, immunophenotyping, flow cytometry), we screened the literature from January 1985 to April 2015 in PubMed and Embase databases and found 1010 articles. A total of 363 were selected and submitted to the expert panel, which selected a final data set of 248 articles to be analyzed. Of these, 160 were focused on clinical and biological issues, 55 were technical articles, and 31 were reviews. These 248 articles were then analyzed according to the 6-variables model and definitively classified. We assessed the literature on flow cytometric immunophenotyping of AL over 3 decades as the first step toward an evidence-based analysis of the impact of this technology on the clinical management of patients with AL.

Proptosis as Initial Presentation of Acute Lymphoblastic Leukemia in a Child with no associated symptoms: A Case Report

Acute lymphocytic leukemia (ALL) is one of the frequent malignancies in pediatrics and involves bone marrow and extramedullary sites. Proptosis as extramedullary involvement of leukemia usually present in acute and chronic myeloid leukemia. It is extremely rare for ALL to present initially as proptosis.Here, a-21-month-old boy was presented with proptosis without any associated symptoms except lymphadenopathy. He was referred with the impression of malignancy from an ophthalmologist. After bone marrow biopsy which showed 33% blast cells, all positive for CD10, CD19, and CD79, the diagnosis of pre-B cell ALL was finally made. His symptoms were improved completely 16 days after starting standard protocol for ALL.Afterone-year follow-up, he was free of any symptoms.According to this initial presentation of ALL and no typical associated symptoms, it is important to make rapid diagnosis and start the treatment in the childhood.

An ERG Enhancer-Based Reporter Identifies Leukemia Cells with Elevated Leukemogenic Potential Driven by ERG-USP9X Feed-Forward Regulation.

Acute leukemia is a rapidly progressing blood cancer with low survival rates. Unfavorable prognosis is attributed to insufficiently characterized subpopulations of leukemia stem cells (LSC) that drive chemoresistance and leukemia relapse. Here we utilized a genetic reporter that assesses stemness to enrich and functionally characterize LSCs. We observed heterogeneous activity of the ERG+85 enhancer-based fluorescent reporter in human leukemias. Cells with high reporter activity (tagBFPHigh) exhibited elevated expression of stemness and chemoresistance genes and demonstrated increased clonogenicity and resistance to chemo- and radiotherapy as compared with their tagBFPNeg counterparts. The tagBFPHigh fraction was capable of regenerating the original cellular heterogeneity and demonstrated increased invasive ability. Moreover, the tagBFPHigh fraction was enriched for leukemia-initiating cells in a xenograft assay. We identified the ubiquitin hydrolase USP9X as a novel ERG transcriptional target that sustains ERG+85-positive cells by controlling ERG ubiquitination. Therapeutic targeting of USP9X led to preferential inhibition of the ERG-dependent leukemias. Collectively, these results characterize human leukemia cell functional heterogeneity and suggest that targeting ERG via USP9X inhibition may be a potential treatment strategy in patients with leukemia. SIGNIFICANCE: This study couples a novel experimental tool with state-of-the-art approaches to delineate molecular mechanisms underlying stem cell-related characteristics in leukemia cells.

Maternal Residential Proximity to Major Roadways and the Risk of Childhood Acute Leukemia: A Population-Based Case-Control Study in Texas, 1995-2011.

Acute leukemia is the most common pediatric malignancy. Some studies suggest early-life exposures to air pollution increase risk of childhood leukemia. Therefore, we explored the association between maternal residential proximity to major roadways and risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Information on cases with acute leukemia (n = 2030) was obtained for the period 1995–2011 from the Texas Cancer Registry. Birth certificate controls were frequency matched (10:1) on birth year (n = 20,300). Three residential proximity measures were assessed: (1) distance to nearest major roadway, (2) residence within 500 meters of a major roadway, and (3) roadway density. Multivariate logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI). Mothers who lived ≤500 meters to a major roadway were not more likely to have a child who developed ALL (OR = 1.03; 95% CI: 0.91–1.16) or AML (OR = 0.84; 95% CI: 0.64–1.11). Mothers who lived in areas characterized by high roadway density were not more likely to have children who developed ALL (OR = 1.06, 95% CI: 0.93–1.20) or AML (OR = 0.83, 95% CI: 0.61–1.13). Our results do not support the hypothesis that maternal proximity to major roadways is strongly associated with childhood acute leukemia. Future assessments evaluating the role of early-life exposure to environmental factors on acute leukemia risk should explore novel methods for directly measuring exposures during relevant periods of development.