Outcomes of children with well-differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731.

Background: Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone.

Patients And Methods: Patients on the Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's stage, tumor histology, and serum alpha-fetoprotein level at diagnosis.

Transcriptional Plasticity Drives Leukemia Immune Escape.

Unlabelled: Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHCII) genes through unknown mechanisms. In this work, we developed CORENODE, a computational algorithm for genome-wide transcription network decomposition that identified a transcription factor (TF) tetrad consisting of IRF8, MYB, MEF2C, and MEIS1, regulating MHCII expression in AML cells. We show that reduced MHCII expression at relapse is transcriptionally driven by combinatorial changes in the expression of these TFs, where MYB and IRF8 play major opposing roles, acting independently of the IFNγ/CIITA pathway.

Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures.

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of .

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of , a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia.

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia.

Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2.

Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma.

Unlabelled: Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies.

Lack of Concordance in Symptomatic Adverse Event Reporting by Children, Clinicians, and Caregivers: Implications for Cancer Clinical Trials.

Purpose: To examine concordance in symptomatic adverse event (AE) grading using the Common Terminology Criteria for Adverse Events (CTCAE 4.0) for clinicians and its patient-reported outcome (PRO) versions for children (Ped-PRO-CTCAE) and caregivers (Ped-PRO-CTCAE [Caregiver]).

Methods: Children age 7-18 years with a first cancer diagnosis, their clinicians, and caregivers completed CTCAE-based measures before starting a treatment course (T1) and after the treatment (T2).

The proteogenomic subtypes of acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing.

Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma.

Purpose: Cyclin-dependent kinases (CDKs) that have critical roles in RNA polymerase II (Pol II)-mediated gene transcription are emerging as therapeutic targets in cancer. We have previously shown that THZ1, a covalent inhibitor of CDKs 7/12/13, leads to cytotoxicity in -amplified neuroblastoma through the downregulation of super-enhancer-associated transcriptional upregulation. Here we determined the effects of YKL-5-124, a novel covalent inhibitor with greater selectivity for CDK7 in neuroblastoma cells.

SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL.

An CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML.

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies , including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing.

The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53.

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance.

Transcription factor competition at the γ-globin promoters controls hemoglobin switching.

BCL11A, the major regulator of fetal hemoglobin (HbF, αγ) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, αβ). To uncover how BCL11A initiates repression, we used CRISPR-Cas9, dCas9, dCas9-KRAB and dCas9-VP64 screens to dissect the γ-globin promoters and identified an activator element near the BCL11A-binding site. Using CUT&RUN and base editing, we demonstrate that a proximal CCAAT box is occupied by the activator NF-Y.

Interdisciplinary care of pediatric oncology patients in Central America and the Caribbean.

Background: Interdisciplinary teamwork supports high-quality cancer care and effective utilization of limited resources. This study purposed to examine the value, structure, process, and effectiveness of interdisciplinary care (IDC) among pediatric oncology providers in low-income and middle-income countries in Central America and the Caribbean.

Methods: A cross-sectional survey was disseminated to pediatric oncology providers at 5 centers participating in the Pediatric Hematology-Oncology Association of Central America.

Subjective Toxicity Profiles of Children in Treatment for Cancer: A New Guide to Supportive Care?

Context: Children and adolescents with cancer experience treatment-related, subjective adverse events (AEs). Identifying distinct groups of patients who predictably experience higher prevalence of AEs could guide patient care.

Objectives: Study aims were to 1) identify groups of children and adolescents reporting AEs using the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE); 2) determine whether demographic and clinical characteristics predict AE group membership; and 3) examine whether AE group membership was related to the distal outcome of psychological stress.

Overgrowth syndromes and new therapies.

Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer.

Variation In State Medicaid Implementation Of The ACA: The Case Of Concurrent Care For Children.

More than 55,000 children die each year in the United States, and hospice is used for very few of them at the end of their lives. Nearly one-third of pediatric deaths are a result of chronic, complex conditions, and the majority of these children are enrolled in Medicaid because of disability status or the severity of their disease. Changes in Medicaid/Children's Health Insurance Program regulations under Section 2302 of the Affordable Care Act require all state Medicaid plans to finance curative and hospice services for children.

Developing and Using a Data Commons for Understanding the Molecular Characteristics of Germ Cell Tumors.

Germ cell tumors (GCTs) are a rare disease, but they account for 15% of all malignancies diagnosed during adolescence. The biological mechanisms underpinning their development are only starting to be explored. Current GCT treatment may be associated with significant toxicity.

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism.

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs.