The late endosome/lysosome (LE/Lys) lipid bis(monoacylglycero)phosphate (BMP) plays major roles in cargo sorting and degradation, regulation of cholesterol and intercellular communication and has been linked to viral infection and neurodegeneration. Although BMP was initially described over fifty years ago, the enzymes regulating its synthesis remain unknown. The first step in the BMP biosynthetic pathway is the conversion of phosphatidylglycerol (PG) into lysophosphatidylglycerol (LPG) by a phospholipase A2 (PLA2) enzyme. Here we report that this enzyme is lysosomal PLA2 (LPLA2). We show that LPLA2 is sufficient to convert PG into LPG in vitro. We show that modulating LPLA2 levels regulates BMP levels in HeLa cells, and affects downstream pathways such as LE/Lys morphology and cholesterol levels. Finally, we show that in a model of Niemann-Pick disease type C, overexpressing LPLA2 alleviates the LE/Lys cholesterol accumulation phenotype. Altogether, we shed new light on BMP biosynthesis and contribute tools to regulate BMP-dependent pathways.

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Multiple myeloma (MM) is a progressive hematological cancer with a 5-year survival rate of 53% (1). Novel therapeutic strategies are being developed to target specific MM surface antigens. Yet, changes in antigen expression through MM progression are poorly understood in the clinic and have not been well characterized in preclinical models. Here, we were interested in understanding how BCMA, CD38, CD138 and HLA-DR surface expression patterns may be affected as MM progresses in preclinical models. To do so, ARH-77 and RPMI-8226 cells were inoculated subcutaneously while MM.1S, MM.1R, U266 and NCI-H929 cells were dosed intravenously into NSG mice. Tumor xenograft or bone marrow, whole blood and spleen were processed for flow cytometry analysis. Antigen expression was measured at different stages of tumor progression as well as in vitro. Soluble BCMA levels were assessed in the mouse serum by ELISA. ARH-77 and RPMI-8226 subcutaneous xenografts show preferential growth when inoculated in PBS and 50% growth factor-reduced Matrigel, respectively. BCMA expression was reduced in both ARH-77 and RPMI-8226 xenografts compared to in vitro culture. CD38 and HLA-DR expression increased as ARH-77/PBS and RPMI-8226/Matrigel tumor volume progressed. All 4 antigens were detected in the bone marrow from MM.1S, MM.1R and U266-bearing mice, as early as 5-6 weeks post intravenous injection. In contrast, antigens were not detected in any tissue from mice injected with NCI-H929, likely indicating failed engraftment. At 5 weeks, antigens were detected in the whole blood and spleen in MM.1S-bearing mice only, suggesting organ invasion and a more advanced disease-stage compared to MM.1R or U266. Experiments are being carried out to test antigen expression in tissue at late-stage tumor progression as well as serum BCMA levels in the intravenous MM models. These data highlight antigen expression differences in MM cells when analyzed in mouse tissue compared to in vitro culture. Like the widely variable expression observed between patients (2, 3), BCMA and CD138 were differentially expressed in the mouse bone marrow between models. Our observations suggest that commonly targeted antigens in MM vary kinetically in vivo and can be measured by flow cytometry. The present findings also support the use of RPMI-8226 and MM.1S cell lines when screening for antigen-specific immunotherapies and combinatorial studies for MM treatment. References: 1.Howlader et al. https://seer.cancer.gov/csr/1975_2017 2.Brudno et al. J Clin Oncol. 2018 3.Kawano et al. Int J Oncol. 2012 Citation Format: Nadege Morisot, Julian Tam, Nicole Dailey, Tina Davis, Jacinda Chen, Janeen Islar, Luxuan Buren, Nitin Patel, Sasha Lazetic, Ivan Chan, James B. Trager, Joanne B. Tan. Surveying surface antigen expression in multiple myeloma preclinical models [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 6004.

Down Syndrome (DS), caused by triplication of human chromosome 21 (Hsa21) is the most common form of intellectual disability worldwide. Recent progress in healthcare has resulted in a dramatic increase in the lifespan of individuals with DS. Unfortunately, most will develop Alzheimer’s disease like dementia (DS-AD) as they age. Understanding similarities and differences between DS-AD and the other forms of the disease – i.e., late-onset AD (LOAD) and autosomal dominant AD (ADAD) – will provide important clues for the treatment of DS-AD. In addition to the APP gene that codes the precursor of the main component of amyloid plaques found in the brain of AD patients, other genes on Hsa21 are likely to contribute to disease initiation and progression. This review focuses on SYNJ1, coding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1). First, we highlight the function of SYNJ1 in the brain. We then summarize the involvement of SYNJ1 in the different forms of AD at the genetic, transcriptomic, proteomic and neuropathology levels in humans. We further examine whether results in humans correlate with what has been described in murine and cellular models of the disease and report possible mechanistic links between SYNJ1 and the progression of the disease. Finally, we propose a set of questions that would further strengthen and clarify the role of SYNJ1 in the different forms of AD.