Cancer-associated genetic alterations induce expression of tumor antigens which can activate CD8+ cytotoxic T cells (CTL), but the microenvironment of established tumors promotes immune tolerance through poorly understood mechanisms1,2. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumor-directed CTL and are effective in some human cancers1. Immune mechanisms also affect treatment outcome and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death (ICD) and other effector mechanisms3,4. Our previous studies revealed that B lymphocytes recruited by CXCL13 into prostate cancer (PC) promote castrate-resistant PC (CRPC) by producing lymphotoxin (LT) which activates an IKKα-Bmi1 module in PC stem cells5,6. Since CRPC is refractory to most therapies, we examined B cell involvement in acquisition of chemotherapy resistance. We focused this study on oxaliplatin, an immunogenic chemotherapeutic3,4 that is effective in aggressive PC7. We found that B cells modulate the response to low dose oxaliplatin, which by inducing ICD promotes tumor-directed CTL activation. Three different mouse PC models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The critical immunosuppressive B cells are plasmocytes that express IgA, IL-10 and PD-L1, whose appearance depends on TGFβ-receptor (TGFβR) signaling. Elimination of these cells, which also infiltrate human therapy-resistant PC, allows CTL-dependent eradication of oxaliplatin-treated tumors.

The regulated translation of localized mRNAs in neurons provides a mechanism for spatially restricting gene expression in a synapsespecific manner. To identify the population of mRNAs present in distal neuronal processes of rodent hippocampal neurons, we grew neurons on polycarbonate filters etched with 3 m pores. Although the neuronal cell bodies remained on the top surface of the filters, dendrites, axons, and glial processes penetrated through the pores to grow along the bottom surface of the membrane where they could be mechanically separated from cell bodies. Quantitative PCR and immunochemical analyses of the process preparation revealed that it was remarkably free of somatic contamination. Microarray analysis of RNA isolated from the processes identified over 100 potentially localized mRNAs. In situ hybridization studies of 19 of these transcripts confirmed that all 19 were present in dendrites, validating the utility of this approach for identifying dendritically localized transcripts. Many of the identified mRNAs encoded components of the translational machinery and several were associated with the RNA-binding protein Staufen. These findings indicate that there is a rich repertoire of mRNAs whose translation can be locally regulated and support the emerging idea that local protein synthesis serves to boost the translational capacity of synapses.

Summary Leukemia stem cells (LSC) play a pivotal role in chronic myeloid leukemia (CML) tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), in part, through alternative splicing of self-renewal and survival genes. To elucidate splice isoform regulators of human BC LSC maintenance, we performed whole transcriptome RNA sequencing; splice isoform-specific qRT-PCR, nanoproteomics, stromal co-culture and BC LSC xenotransplantation analyses. Cumulatively, these studies show that alternative splicing of multiple pro-survival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSC that are quiescent in the marrow niche and contribute to therapeutic resistance. Notably, a novel pan-BCL2 inhibitor, sabutoclax, renders marrow niche-resident BC LSC sensitive to TKIs at doses that spare normal progenitors. These findings underscore the importance of alternative BCL2 family splice isoform expression in BC LSC maintenance and suggest that combinatorial inhibition of pro-survival BCL2 family proteins and BCR-ABL may eliminate dormant LSC and obviate resistance.

Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the steroidogenic factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (؉͞؊) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 ؉͞؊ mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress. P hysiological adaptation to infection, injury, and starvation requires an endocrine stress response that is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In instances of adrenal crisis or adrenal insufficiency, the inability to mount an adequate response to acute physiological stress can lead to morbidity (1). In response to stress, adrenal secretion of glucocorticoids is initiated by the hypothalamic neuropeptide corticotropin releasing hormone (CRH), which stimulates pituitary release of adrenocorticotropic hormone (ACTH). Activation of ACTH receptors in the adrenal cortex promotes glucocorticoid synthesis and secretion; glucocorticoids then act on a wide range of target tissues (2). Human diseases associated with an impaired stress response arise from either primary defects in the adrenal or secondary defects at the level of the hypothalamus or pituitary. Primary adrenal insufficiency is most commonly due to bilateral adrenal gland destruction resulting from autoimmune and infectious diseases, such as AIDS and tuberculosis (1). Other forms of primary adrenal insufficiency result from inherited defects in cortisol biosynthesis and manifest as adrenal hyperplasia because of lack of adrenal feedback in the HPA axis (1). Finally, rarer forms of familial adrenal insufficiency are associated with mutations in members of the nuclear receptor superfamily. For example, mutations in the X-linked gene Dax1 lead to abnormal adrenal development resulting in adrenal hypoplasia, as well as hypogonadotropic hypogonadism (3-5).A similar, but less well-characterized form of adrenal insufficiency was revealed by the analysis of a single patient with a heterozygous mutation in the orphan nuclear receptor steroidogenic factor-1 (SF-1). This individual was diagnosed with primary adrenal insufficiency as well as XY sex reversal, suggesting that SF-1 functions in a dose-dependent manner in humans (6). A large number...