ABSTRACT The link between cancer maintenance and an ability to sustain continued growth through stresses conferred by the cancer state itself is growing. However, there are significant gaps in our understanding of how this stress is managed, particularly at the level of cancer initiating cells. Here, we identify proteins comprising the dynamic, stress-adaptive ribonucleoprotein complexes known as stress granules (SG) to be enriched among the factors essential for leukemic stem cell (LSC)-driven leukemic propagation. Focusing on core SG nucleator G3BP1, we dissect the role of SGs in human acute myeloid leukemia (AML), their targetability, and the mechanisms they govern to uncover a novel propensity for AML, and in particular LSC-enriched fractions, to prime the expression of SG components, form SGs with greater fidelity and to be reliant on their establishment and continued integrity for LSC maintenance. We further unveil the transcript and protein interactome of G3BP1 in the AML context and show that consolidated control of innate immune signaling, and apoptosis repression is executed through regional binding specificity of G3BP1 to highly structured 3’UTRs and cooperation with the RNA helicase UPF1 to mediate transcript decay in SGs. Altogether our findings advance novel fundamental principles of stress adaptation exploited in AML and LSCs that may extend to other cancers and uncover SGs as a novel axis for therapy development.

Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organs. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposes transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue-remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Living with HIV infection is associated with early onset of aging-related chronic conditions, sometimes described as accelerated aging. Epigenetic DNA methylation patterns can evaluate acceleration of biological age relative to chronological age. The impact of initial HIV infection on five epigenetic measures of aging was examined before and approximately 3 years after HIV infection in the same individuals (n=102). Significant epigenetic age acceleration (median 1.9-4.8 years) and estimated telomere length shortening (all p≤ 0.001) were observed from pre-to post-HIV infection, and remained significant in three epigenetic measures after controlling for T cell changes. No acceleration was seen in age- and time interval-matched HIV-uninfected controls. Changes in genome-wide co-methylation clusters were also significantly associated with initial HIV infection (p≤ 2.0 × 10-4). These longitudinal observations clearly demonstrate an early and substantial impact of HIV infection on the epigenetic aging process, and suggest a role for HIV itself in the earlier onset of clinical aging.
© 2022 The Author(s).

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. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.
Copyright © 2019 Elsevier Inc. All rights reserved.