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Abstract

Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

Authors

Hal M. Hoffman, Lori Broderick

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Abstract

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein–signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.

Authors

Björn Tampe, Désirée Tampe, Gunsmaa Nyamsuren, Friederike Klöpper, Gregor Rapp, Anne Kauffels, Thomas Lorf, Elisabeth M. Zeisberg, Gerhard A. Müller, Raghu Kalluri, Samy Hakroush, Michael Zeisberg

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Abstract

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.

Authors

Natalia Rodriguez-Muela, Andrey Parkhitko, Tobias Grass, Rebecca M. Gibbs, Erika M. Norabuena, Norbert Perrimon, Rajat Singh, Lee L. Rubin

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Abstract

Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells. The transcriptomes of CD30+ GC and EF B cells largely overlapped, sharing a strong MYC signature, but were strikingly different from conventional GC B cells and memory B and plasma cells, respectively. CD30+ GC B cells represent MYC+ centrocytes redifferentiating into centroblasts; CD30+ EF B cells represent active, proliferating memory B cells. HRS cells shared typical transcriptome patterns with CD30+ B cells, suggesting that they originate from these lymphocytes or acquire their characteristic features during lymphomagenesis. By comparing HRS to normal CD30+ B cells we redefined aberrant and disease-specific features of HRS cells. A remarkable downregulation of genes regulating genomic stability and cytokinesis in HRS cells may explain their genomic instability and multinuclearity.

Authors

Marc A. Weniger, Enrico Tiacci, Stefanie Schneider, Judith Arnolds, Sabrina Rüschenbaum, Janine Duppach, Marc Seifert, Claudia Döring, Martin-Leo Hansmann, Ralf Küppers

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Abstract

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E–deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.

Authors

Jakob Voelkl, Trang T.D. Luong, Rashad Tuffaha, Katharina Musculus, Tilman Auer, Xiaoming Lian, Christoph Daniel, Daniel Zickler, Beate Boehme, Michael Sacherer, Bernhard Metzler, Dietmar Kuhl, Maik Gollasch, Kerstin Amann, Dominik N. Müller, Burkert Pieske, Florian Lang, Ioana Alesutan

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Abstract

The transcription factor GATA6 has been shown to be important for lung development and branching morphogenesis in mouse models, but its role in human lung development is largely unknown. Here, we studied the role of GATA6 during lung differentiation using human pluripotent stem cells. We found that the human stem cell lines most efficient at generating NKX2.1+ lung progenitors express lower endogenous levels of GATA6 during endoderm patterning and that knockdown of GATA6 during endoderm patterning increased the generation of these cells. Complete ablation of GATA6 resulted in the generation of lung progenitors displaying increased cell proliferation with up to a 15-fold expansion compared with control cells, whereas the null cell line displayed a defect in further development into mature lung cell types. Furthermore, transgenic expression of GATA6 at the endoderm anteriorization stage skewed development toward a liver fate at the expense of lung progenitors. Our results suggest a critical dosage effect of GATA6 during human endoderm patterning and a later requirement during terminal lung differentiation. These studies offer an approach of modulating GATA6 expression to enhance the production of lung progenitors from human stem cell sources.

Authors

Chia-Min Liao, Somdutta Mukherjee, Amita Tiyaboonchai, Jean Ann Maguire, Fabian L. Cardenas-Diaz, Deborah L. French, Paul Gadue

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Abstract

The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II–induced (Ang II–induced) pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline, whereas Ang II–induced effector T cell (Teff) infiltration was inhibited. To investigate the role of Treg Nox2, we generated a mouse line with CD4-targeted Nox2 deficiency (Nox2fl/flCD4Cre+). These animals showed inhibition of Ang II–induced hypertension and cardiac remodeling related to increased tissue-resident Tregs and reduction in infiltrating Teffs, including Th17 cells. The protection in Nox2fl/flCD4Cre+ mice was reversed by anti-CD25 antibody depletion of Tregs. Mechanistically, Nox2–/y Tregs showed higher in vitro suppression of Teff proliferation than WT Tregs, increased nuclear levels of FoxP3 and NF-κB, and enhanced transcription of CD25, CD39, and CD73. Adoptive transfer of Tregs confirmed that Nox2-deficient cells had greater inhibitory effects on Ang II–induced heart remodeling than WT cells. These results identify a previously unrecognized role of Nox2 in modulating suppression of Tregs, which acts to enhance hypertension and cardiac remodeling.

Authors

Amber Emmerson, Silvia Cellone Trevelin, Heloise Mongue-Din, Pablo D. Becker, Carla Ortiz, Lesley A. Smyth, Qi Peng, Raul Elgueta, Greta Sawyer, Aleksandar Ivetic, Robert I. Lechler, Giovanna Lombardi, Ajay M. Shah

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Abstract

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

Authors

David Boutboul, Hye Sun Kuehn, Zoé Van de Wyngaert, Julie E. Niemela, Isabelle Callebaut, Jennifer Stoddard, Christelle Lenoir, Vincent Barlogis, Catherine Farnarier, Frédéric Vely, Nao Yoshida, Seiji Kojima, Hirokazu Kanegane, Akihiro Hoshino, Fabian Hauck, Ludovic Lhermitte, Vahid Asnafi, Philip Roehrs, Shaoying Chen, James W. Verbsky, Katherine R. Calvo, Ammar Husami, Kejian Zhang, Joseph Roberts, David Amrol, John Sleaseman, Amy P. Hsu, Steven M. Holland, Rebecca Marsh, Alain Fischer, Thomas A. Fleisher, Capucine Picard, Sylvain Latour, Sergio D. Rosenzweig

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Abstract

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9–/– autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

Authors

Purvi Mande, Bahar Zirak, Wei-Che Ko, Keyon Taravati, Karen L. Bride, Tia Y. Brodeur, April Deng, Karen Dresser, Zhaozhao Jiang, Rachel Ettinger, Katherine A. Fitzgerald, Michael D. Rosenblum, John E. Harris, Ann Marshak-Rothstein

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Abstract

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Authors

Gina A. Montealegre Sanchez, Adam Reinhardt, Suzanne Ramsey, Helmut Wittkowski, Philip J. Hashkes, Yackov Berkun, Susanne Schalm, Sara Murias, Jason A. Dare, Diane Brown, Deborah L. Stone, Ling Gao, Thomas Klausmeier, Dirk Foell, Adriana A. de Jesus, Dawn C. Chapelle, Hanna Kim, Samantha Dill, Robert A. Colbert, Laura Failla, Bahar Kost, Michelle O’Brien, James C. Reynolds, Les R. Folio, Katherine R. Calvo, Scott M. Paul, Nargues Weir, Alessandra Brofferio, Ariane Soldatos, Angelique Biancotto, Edward W. Cowen, John J. Digiovanna, Massimo Gadina, Andrew J. Lipton, Colleen Hadigan, Steven M. Holland, Joseph Fontana, Ahmad S. Alawad, Rebecca J. Brown, Kristina I. Rother, Theo Heller, Kristina M. Brooks, Parag Kumar, Stephen R. Brooks, Meryl Waldman, Harsharan K. Singh, Volker Nickeleit, Maria Silk, Apurva Prakash, Jonathan M. Janes, Seza Ozen, Paul G. Wakim, Paul A. Brogan, William L. Macias, Raphaela Goldbach-Mansky

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Abstract

EZH2-mediated epigenetic regulation of T cell differentiation and regulatory T cell function has been described previously; however, the role of EZH2 in T cell–mediated anti-tumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in regulatory T cells (FoxP3creEZH2fl/fl mice) leads to robust anti-tumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the regulatory T cells and enhanced cytotoxic activity of effector T cells. We observed that ipilimumab (anti–CTLA-4) increased EZH2 expression in peripheral T cells from treated patients. We hypothesized that inhibition of EZH2 expression in T cells would increase the effectiveness of anti–CTLA-4 therapy, which we tested in murine models. Collectively, our data demonstrated that modulating EZH2 expression in T cells can improve anti-tumor responses elicited by anti–CTLA-4 therapy, which provides a strong rationale for a combination trial of CPI-1205 plus ipilimumab.

Authors

Sangeeta Goswami, Irina Apostolou, Jan Zhang, Jill Skepner, Swetha Anandhan, Xuejun Zhang, Liangwen Xiong, Patrick Trojer, Ana Aparicio, Sumit K. Subudhi, James P. Allison, Hao Zhao, Padmanee Sharma

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Abstract

Painful signals are transmitted by mutisynaptic glutamatergic pathways. Their first synapse between primary nociceptors and excitatory spinal interneurons gates sensory load. Glutamate release herein is orchestrated by Ca2+ sensor proteins with neuronal calcium-binding protein 2 (NECAB2) being particularly abundant. However, neither the importance of NECAB2+ neuronal contingents in dorsal root ganglia (DRG) and spinal cord nor function-determination by NECAB2 has been defined. A combination of histochemistry and single-cell RNA-seq showed NECAB2 in small/medium-sized C- and Aδ D-hair low threshold mechanoreceptors in DRG, as well as in protein kinase γ-positive excitatory spinal interneurons. NECAB2 was downregulated by peripheral nerve injury, offering the hypothesis that NECAB2 loss-of-funtion could limit pain sensation. Indeed, Necab2–/– mice reached a pain-free state significantly faster after peripheral inflammation than wild-type littermates. Genetic access to transiently-activated neurons revealed that a mediodorsal cohort of NECAB2+ neurons mediates inflammatory pain in mouse spinal dorsal horn. Here, besides dampening excitatory transmission in spinal interneurons, NECAB2 limited pronociceptive brain-derived neurotrophic factor release from sensory afferents. Hox8b-dependent reinstatement of NECAB2 expression in Necab2–/– mice then demonstrated that spinal/DRG NECAB2 alone could control inflammation-induced sensory hyperensitivity. Overall, we identify NECAB2 as a critical component of pro-nociceptive pain signaling whose inactivation offers substantial pain relief.

Authors

Ming-Dong Zhang, Jie Su, Csaba Adori, Valentina Cinquina, Katarzyna Malenczyk, Fatima Girach, Changgeng Peng, Patrik Ernfors, Peter Löw, Lotta Borgius, Ole Kiehn, Masahiko Watanabe, Mathias Uhlén, Nicholas Mitsios, Jan Mulder, Tibor Harkany, Tomas Hökfelt

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Abstract

T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine SDF-1α triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.

Authors

Carola Ledderose, Kaifeng Liu, Yutaka Kondo, Christian J. Slubowski, Thomas Dertnig, Sara Denicoló, Mona Arbab, Johannes Hubner, Kirstin Konrad, Mahtab Fakhari, James A. Lederer, Simon C. Robson, Gary A. Visner, Wolfgang G. Junger

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Abstract

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard Asparaginase-based therapy for childhood acute lymphoblastic leukaemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids or Asparaginase indicated that loss of intracellular ATP generation is a significant factor. In isolated mouse pancreatic acinar cells or cell clusters, we now report that removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or Asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data we suggest that galactose feeding may be used to protect against AP.

Authors

Shuang Peng, Julia V. Gerasimenko, Tetyana M. Tsugorka, Oleksiy Gryshchenko, Sujith Samarasinghe, Ole H. Petersen, Oleg V. Gerasimenko

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Abstract

PRDM16 is a transcriptional co-regulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR-domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling and repressed inflammation, while sPrdm16 supported B-cell development biased towards marginal zone B-cells and induced an inflammatory signature. In a mouse model of human MLL-AF9 leukemia fPrdm16 extended latency, while sPrdm16 shortened latency and induced a strong inflammatory signature, including several cytokines and chemokines that are associated with myelodysplasia and with a worse prognosis in human AML. Finally, in human NPM1-mutant and in MLL-translocated AML high expression of PRDM16, which negatively impacts outcome, was associated with inflammatory gene expression, thus corroborating the mouse data. Our observations demonstrate distinct roles for Prdm16 isoforms in normal HSCs and AML, and identify sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.

Authors

David J. Corrigan, Larry L. Luchsinger, Mariana Justino de Almeida, Linda J. Williams, Alexandros Strikoudis, Hans-Willem Snoeck

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June 2018

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June 2018 Issue

On the cover:
Copy number variations contribute to breast cancer spread

In this issue, Bao et al. investigated the evolution of breast cancer spread to lymph nodes by sequencing laser-captured single cells from morphologically distinct areas of primary breast tumors and metastases, revealing that metastatic capability correlated with copy number variations in specific genomic regions. The cover image visualizes the sequencing of single cells, a technique enabling analyses of clonal evolution that account for cell type, spatial location, and within-tumor genetic variation. Image credit: Henrik Ditzel and Li Bao.

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Jci tm 2018 06

June 2018 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

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Review Series - More

Cellular senescence in human disease

Series edited by Jan van Deursen

Cellular senescence is a normal consequence of aging, resulting from lifelong accumulation of DNA damage that triggers an end to cell replication. Although senescent cells no longer divide, they persist in their tissue of origin and develop characteristics that can hasten and exacerbate age-related disease. This series addresses the contribution of cellular senescence to cardiovascular, neurodegenerative, and arthritic disorders as well as the senescent phenotypes in various tissues and cell types. In addition to their cell-intrinsic effects, senescent cells develop the ability to negatively influence healthy neighboring cells and immune cells by secreting senescence-associated set of cytokines and mediators known as the SASP. These reviews also highlight ongoing efforts to accurately identify, target, and eliminate senescent cells or otherwise combat their deleterious effects in disease. One day, this work may provide the basis for therapies targeting aging cells in multiple organs.

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