Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner.

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.

Education Scholarship Assessment Reconsidered: Expansion of Glassick's Criteria to Incorporate Health Equity.

ABSTRACT: Recent events have ignited widespread attention to structural racism and implicit bias throughout the U.S. health care system and medical institutions, resulting in a call for antiracism approaches to advance health equity. Medical education leaders are well positioned to advance health equity, not only through their training of fellows, residents, and medical students, but also in their approach to scholarship. Education scholarship drives innovation and critical evaluation of current practices; it impacts and intersects with multiple factors that have the potential to reduce health inequities. Thus, it is critical to prioritize the assessment of education scholarship through a health equity lens. Medical education scholarly dissemination has markedly expanded over the past 2 to 3 decades, yet medical educators have continued to embrace Boyer's and Glassick and colleagues' definitions of scholarship. The authors propose an approach to medical education scholarship assessment that expands each of Glassick's 6 existing criteria to address health inequities and adds health equity as a seventh criterion. With this, medical educators, researchers, reviewers, and others can consider how education scholarship affects diverse populations and settings, direct educational products and scholarship to address health inequities, and raise the importance of advancing health equity in medical education scholarship. By expanding and standardizing the assessment of scholarship to incorporate health equity, the medical education community can foster a cultural shift that brings health equity to the forefront of education scholarship.

Single-cell lineage capture across genomic modalities with CellTag-multi reveals fate-specific gene regulatory changes.

Complex gene regulatory mechanisms underlie differentiation and reprogramming. Contemporary single-cell lineage-tracing (scLT) methods use expressed, heritable DNA barcodes to combine cell lineage readout with single-cell transcriptomics. However, reliance on transcriptional profiling limits adaptation to other single-cell assays. With CellTag-multi, we present an approach that enables direct capture of heritable random barcodes expressed as polyadenylated transcripts, in both single-cell RNA sequencing and single-cell Assay for Transposase Accessible Chromatin using sequencing assays, allowing for independent clonal tracking of transcriptional and epigenomic cell states. We validate CellTag-multi to characterize progenitor cell lineage priming during mouse hematopoiesis. Additionally, in direct reprogramming of fibroblasts to endoderm progenitors, we identify core regulatory programs underlying on-target and off-target fates. Furthermore, we reveal the transcription factor Zfp281 as a regulator of reprogramming outcome, biasing cells toward an off-target mesenchymal fate. Our results establish CellTag-multi as a lineage-tracing method compatible with multiple single-cell modalities and demonstrate its utility in revealing fate-specifying gene regulatory changes across diverse paradigms of differentiation and reprogramming.

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis.

Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development in mice, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition to adult hematopoiesis, and it drives the expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations expand simultaneously. These changes had a surprisingly little effect on the production of more differentiated blood cells. Cellular indexing of transcriptomes and epitopes by sequencing resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally and phenotypically defined MPP populations may affect interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation.

BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes.

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer. SIGNIFICANCE: We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance. Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches. This article is highlighted in the In This Issue feature, p. 85.

Natural progression of an unresected supratentorial ependymoma.

Ependymomas are rare gliomas that have been associated with a poor outcome despite aggressive therapy including surgery, chemotherapy and radiation therapy. We present a case report of a 16-year-old male with an untreated supratentorial ependymoma that lay dormant for 15 years without significant morbidity. Supratentorial ependymomas are thought to have a better outcome than infratentorial ependymomas, primarily because of the increased likelihood of achieving a gross total resection in the supratentorial space. Our case report suggests that the improved outcome may be due in part to the biologically benign nature of some supratentorial ependymomas. This highly unusual case illustrates the unpredictable heterogeneity of pediatric ependymomas.

Air quality and pediatric asthma-related emergencies.

BACKGROUND: Previous studies suggest a relationship between air pollutants, aeroallergens, and asthma exacerbations. OBJECTIVE: To simultaneously examine the role of seasonality, air quality, aeroallergens, and climate on asthma-related pediatric emergency department (ED) visits. METHODS: A retrospective 4-year study of asthma-related ED visits was conducted. RESULTS: September had the highest number of visits (p < 0.01). There were lower temperatures and precipitation (p < 0.01) and higher tree and weed pollen levels (p = 0.05) on days with more visits (p = 0.05), while grass pollen, mold, ozone, NO2, and PM2.5 levels showed no significant differences. CONCLUSIONS: Asthma-related visits were associated with aeroallergens and climatic factors and not air-quality factors.

Patient, home residence, and neighborhood characteristics in pediatric emergency department visits for asthma.

OBJECTIVE: To identify patient, home residence, and neighborhood characteristics of children with asthma-related emergency department visits. METHODS: Medical records of children with one (group A) or more than one (group B) asthma-related pediatric emergency department visit were reviewed. RESULTS: A significantly higher percentage of group B had Medicaid insurance (p = 0.04), history of asthma-related hospitalizations (p = 0.04), and passive tobacco smoke exposure (p = 0.03). Neighborhood characteristics were similar between the two groups. CONCLUSIONS: Smoking cessation counseling and close monitoring of patients with a history of asthma-related hospitalizations and patients with Medicaid insurance may be helpful in decreasing emergency department visits.

A 5-month-old boy with recurrent respiratory infections, failure to thrive, and borderline elevated sweat chloride levels.

Both severe combined immunodeficiency (SCID) and cystic fibrosis (CF) may present in infancy with a history of respiratory infections and failure to thrive. Elevated sweat chloride levels on multiple sweat tests is diagnostic of CF; transient elevation of sweat chloride has been reported in patients with hypogammaglobulinemia and antibody deficiency without CF. This article presents a case report of a 5-month-old boy with recurrent respiratory infections, failure to thrive, and two borderline elevated sweat test levels. Laboratory evaluation including testing for CF as well as immune deficiency was performed in this patient. Two borderline abnormal sweat chloride tests together with isolation of Pseudomonas from the airway caused clinicians initially to suspect CF; however, mutation in gene coding for the gamma-chain of the IL-2 receptor and a negative CF genetic mutation analysis ultimately led to the final diagnosis of SCID. It is essential to make the diagnosis of SCID as early as possible because infants with SCID who do not undergo reconstitution of their immune system universally die in infancy because of infection. Early diagnosis and intervention can lead to an excellent prognosis in a previously fatal disease.

Erythropoietic protoporphyria masquerading as angioedema in a 4-year-old female.

Angioedema is a common presentation with a broad differential, including rare disorders with which an allergist must be familiar. Our objective was to report a case of swelling of the hands and feet mimicking angioedema with hepatomegaly in a 4-year-old girl. The patient was evaluated for painful swelling of the hands and feet after exposure to sun. Examination revealed edema and erythema of the extremities and hepatomegaly. Laboratory evaluation included elevated liver transaminases and plasma protoporphyrin, with normal urine porphyrins. Liver biopsy confirmed the diagnosis of erythropoietic protoporphyria, a disorder of heme biosynthesis in which patients may present with photosensitivity and angioedema. It is important for allergists to recognize this entity in patients with cutaneous disorders of unclear etiology in order to prevent possible life-threatening sequelae.