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Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

College students are a vulnerable population to food insecurity (FI), which has significant implications for academic and health outcomes. The aims of this study were to explore the meaning of FI and its impact on students’ lived experiences and food decisions, facilitators and barriers to food access as a student, and students’ proposed solutions to address FI. Semi-structured, qualitative interviews were conducted with thirty students from a large, public land grant university in the Southeast United States. Grounded theory methodology was utilized with a constant comparative coding strategy to guide thematic analysis. Nine main themes emerged. Themes included the perceived meaning of FI, students’ lived experience with FI, and food related coping strategies and decisions. Facilitators to food access were found to be social-networks and on-campus resources, while barriers to food access included financial burden of higher education, and stigma and social comparison. Proposed solutions to FI aligned with two main themes: food access solutions and information access solutions. Both of these themes included multiple subthemes that provided specific suggestions to address food insecurity for students. The findings aid in understanding the complex lived experience of FI and can inform future efforts to center student experiences, perceptions, and feedback into institutional frameworks to best meet student needs.

Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.

Cancer cells can survive chemotherapy and drive lethal relapse if they avoid cell death in conditions of 1) DNA damage and/or mitotic stress caused by treatment; 2) nutrient depletion. We and others have previously shown that the breast cancers most likely to survive chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, contrasting with 263 months for TP53 mutant tumors. TP53 wild type cells survive stress by entering a state of arrest and cellular senescence. But to persist in senescence, cells must survive in limited access to vasculature and nutrient sources while also supporting a high metabolic burden that includes production of cytokines and chemokines that drive pro-tumorigenic phenotypes and relapse. We previously showed a novel cannibalism phenotype of chemotherapy induced senescent cells. Engulfment occurred after exposure to different chemotherapy drugs in vitro, in 9 different cell lines, and in vivo in syngeneic mouse mammary tumor models. Engulfed prey cells were processed to the lysosomes of predator cells and broken down. While we showed the phenotype was unrelated to entosis, and senescent cells expressed many phagocytosis/macrophage related genes, the basic mechanisms of the engulfment are unknown. Here, we use biosensors and live cell imaging to delineate the steps of whole cell engulfment in cells that have entered senescence to survive chemotherapy. We show predator cell filamentous actin was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species showed increased concentration and localization of predator PI(4)P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a burst of PI(3)P before internalization. PIK3C2B, an enzyme responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, these data demonstrate the mechanism of cellular cannibalism used by breast cancer cells to survive chemotherapy. Citation Format: Wesley D. Frey, Ashlyn Anderson, Julie Nguyen, Emma Cowles, James Jackson. Chemotherapy induced cellular cannibalism is mediated by phosphoinositide species and clathrin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1576.

Non-immune roles of Regulatory T cells (Tregs) have been described across various tissues. However, the mechanisms by which T cells regulate the bone marrow in myeloproliferative neoplasms lack resolution. Recently, we outlined how Tregs in bone marrow condition the stromal cell niche and enhance hematopoietic support via IL-10 secretion. A hallmark of leukemic progression is the increase in pro-inflammatory cytokines and cellular inflammation. In this study, we demonstrate that this inflammatory milieu promotes pathogenic skewing of both regulatory and effector T cells. We performed a comprehensive characterization of the CD4 T cell compartment in myeloproliferative neoplasms such as chronic myeloid leukemia (CML) and we found that Tregs are unstable and dysregulated the leukemic marrow. This contributes to a phenotype of immune activation as well as an increase of pathogenic inflammatory T cells. Specifically, our findings reveal that Treg Th17 ratios are disrupted in leukemia and that Th17 cells influence disease progression. Additionally, we found that Treg-secreted IL10 has beneficial effects on the functions of healthy and diseased mesenchymal stromal cells (MSCs). We demonstrate that restoring Treg function and expanding their IL10 production can be used therapeutically to delay leukemic burden. Our results support the hypothesis that Tregs are compromised during leukemic progression as a consequence of pro-inflammatory cytokines from the myeloid associated disease. These findings highlight how the Treg Th17 balance regulates disease progression. Furthermore, these studies provide an avenue by which Treg secreted IL10 can be used for therapeutic intervention in the context of heme malignancy.