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1
Hewitt, Kyle J., Suhita Ray, Srinivas Chava, and Linda Chee. "The Samd14 Sterile Alpha Motif Domain Promotes Stress-Induced Cellular Signaling and Survival." Blood 134, Supplement_1 (November 13, 2019): 1184. http://dx.doi.org/10.1182/blood-2019-131228.
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More than 200 mammalian proteins contain Sterile Alpha Motif (SAM) domains. While some of these domains are reported to mediate protein, lipid or RNA binding, the majority have not been analyzed. Our prior work discovered that Samd14, a SAM-domain containing protein, was transcriptionally activated by the GATA2 and Scl/TAL1-occupied Samd14 enhancer (Samd14-Enh). Deletion of Samd14-Enh lowers Samd14 expression in mouse bone marrow and spleen and causes lethality in a mouse model of severe hemolytic anemia. In anemia, stress erythroid progenitors respond to a multitude of paracrine signals, including erythropoietin (Epo) and stem cell factor (SCF), to induce rapid expansion and differentiation until homeostasis is re-established. Mechanistic analyses revealed that Samd14 regulates SCF/c-Kit signaling, erythroid progenitor function and promotes erythrocyte regeneration in anemia. Ex vivo, Samd14-Enh-/- erythroid progenitors (CD71+Ter119-Kit+) exhibited 2.1-fold and 1.6-fold lower phospho (Serine 473) AKT (pAKT) vs. WT in response to 5 min and 10 min SCF stimulation, respectively. To rigorously establish whether the Samd14-Enh deletion reduces anemia-dependent c-Kit signaling by lowering Samd14 levels in erythroid progenitors, we restored Samd14 expression in Samd14-Enh-/- primary erythroid precursor cells. Defective SCF/c-Kit signaling in Samd14-Enh-/- spleen progenitors could be rescued by reestablishing expression of Samd14. To test the role of the SAM domain in Samd14-mediated promotion of stress-induced erythroid progenitor function, we generated a SAM-domain deleted construct of Samd14 (Samd14 Δ SAM) to replace endogenous expression in cells from Samd14-Enh-deleted bone marrow and spleen ex vivo. In colony assays, full-length Samd14 increased GFP+ colony formation 2.7-fold, whereas there was no significant increase in colonies when expressing Samd14 Δ SAM vs. EV. Compared to expression of full-length Samd14, Samd14 Δ SAM exhibited 1.9-fold fewer (p=0.0006) BFU-E colonies (Figure 4B). Together, these results indicated that the Samd14 SAM domain is required for maximal promotion of colony forming ability, cell signaling and survival of erythroid progenitors. As the Samd14 SAM domain mediates SCF/c-Kit signaling, and cells lacking Samd14-Enh have impaired c-Kit signaling following anemia, this protein motif controls anemia-dependent erythroid progenitor cell genesis and/or function. Ongoing analyses to fuse the SAM structural domains of related proteins Neurabin-1 and SHIP-2 will test the sequence requirements of the Samd14 SAM domain on c-Kit signaling and stress erythroid progenitor function. These findings reveal a vital SAM domain-dependent molecular mechanism in stress erythroid progenitors whereby a GATA2 and anemia-activated protein facilitates SCF/c-Kit signaling during regenerative erythropoiesis. Given the importance of GATA2 and GATA2-dependent mechanisms in hematopoiesis, determining the role of the GATA2-Samd14-c-Kit axis in hematologic diseases may reveal unique functions. Disclosures No relevant conflicts of interest to declare.
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Ray, Suhita, Linda Chee, Daniel R. Matson, Nick Y. Palermo, Emery H. Bresnick, and Kyle J. Hewitt. "Sterile α-motif domain requirement for cellular signaling and survival." Journal of Biological Chemistry 295, no. 20 (April 2, 2020): 7113–25. http://dx.doi.org/10.1074/jbc.ra119.011895.
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Hundreds of sterile α-motif (SAM) domains have predicted structural similarities and are reported to bind proteins, lipids, or RNAs. However, the majority of these domains have not been analyzed functionally. Previously, we demonstrated that a SAM domain-containing protein, SAMD14, promotes SCF/proto-oncogene c-Kit (c-Kit) signaling, erythroid progenitor function, and erythrocyte regeneration. Deletion of a Samd14 enhancer (Samd14–Enh), occupied by GATA2 and SCL/TAL1 transcription factors, reduces SAMD14 expression in bone marrow and spleen and is lethal in a hemolytic anemia mouse model. To rigorously establish whether Samd14–Enh deletion reduces anemia-dependent c-Kit signaling by lowering SAMD14 levels, we developed a genetic rescue assay in murine Samd14–Enh−/− primary erythroid precursor cells. SAMD14 expression at endogenous levels rescued c-Kit signaling. The conserved SAM domain was required for SAMD14 to increase colony-forming activity, c-Kit signaling, and progenitor survival. To elucidate the molecular determinants of SAM domain function in SAMD14, we substituted its SAM domain with distinct SAM domains predicted to be structurally similar. The chimeras were less effective than SAMD14 itself in rescuing signaling, survival, and colony-forming activities. Thus, the SAMD14 SAM domain has attributes that are distinct from other SAM domains and underlie SAMD14 function as a regulator of cellular signaling and erythrocyte regeneration.
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Ray, Suhita, Linda Chee, Nicholas T. Woods, and Kyle J. Hewitt. "Functional Requirements of a Samd14-Capping Protein Interaction in Stress Erythropoiesis." Blood 138, Supplement 1 (November 5, 2021): 288. http://dx.doi.org/10.1182/blood-2021-152898.
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Abstract Stress erythropoiesis describes the process of accelerating red blood cell (RBC) production in anemia. Among a number of important mediators of stress erythropoiesis, paracrine signals - involving cooperation between SCF/c-Kit signaling and other signaling inputs - are required for the activation/function of stress erythroid progenitors. Whereas many critical factors required to drive erythropoiesis in normal physiological conditions have been described, whether distinct mechanisms control developmental, steady-state, and stress erythropoiesis in anemia is poorly understood. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated in a model of acute hemolytic anemia induced by the RBC-lysing chemical phenylhydrazine. Samd14 is regulated by GATA binding transcription factors via an intronic enhancer (Samd14-Enh). In a mouse knockout of Samd14-Enh (Samd14-Enh -/-), we established that the Samd14-Enh is dispensable for steady-state erythropoiesis but is required for recovery from severe hemolytic anemia. Samd14 promotes c-Kit signaling in vivo and ex vivo, and the SAM domain of Samd14 facilitates c-Kit-mediated cellular signaling and stress progenitor activity. In addition, the Samd14 SAM domain is functionally distinct from closely related SAM domains, which demonstrates a unique role for this SAM domain in stress signaling and cell survival. In our working model, Samd14-Enh is part of an ensemble of anemia-responsive enhancers which promote stress erythroid progenitor activity. However, the mechanism underlying Samd14's role in stress erythropoiesis is unknown. To identify potential Samd14-interacting proteins that mediate its function, we performed immunoprecipitation-mass spectrometry on the Samd14 protein. We found that Samd14 interacted with α- and β heterodimers of the F-actin capping protein (CP) complex independent of the SAM domain. CP binds to actin during filament assembly/disassembly and plays a role in cell morphology, migration, and signaling. Deleting a 17 amino acid sequence near the N-terminus of Samd14 disrupted the Samd14-CP interaction. However, mutating the canonical RxR of the CP interaction (CPI) motif, which is required for CP-binding in other proteins, does not abrogate the Samd14-CP interaction. Moreover, replacing this sequence with the canonical CPI domain of CKIP-1 completely disrupts the interaction, indicating that other sequence features are required to maintain the Samd14-CP complex. Ex vivo knockdown of the β-subunit of CP (CPβ), which disrupts the integrity of the CP complex, decreased the percentage of early erythroid precursors (p<0.0001) and decreased (3-fold) progenitor activity as measured by colony formation assays (similar to knockdown of Samd14). Taken together, these data indicate that Samd14 interacts with CP via a unique CP binding (CPB) domain, and that the CP complex coordinates erythroid differentiation in stress erythroid progenitors. To test the function of the Samd14-CP complex, we designed an ex vivo genetic complementation assay to express Samd14 lacking the CPB-domain (Samd14∆CPB) in stress erythroid progenitors isolated from anemic Samd14-Enh -/- mice. Phospho-AKT (Ser473) and phospho-ERK (Thr202/Tyr204) levels in Samd14∆CPB were, respectively, 2.2 fold (p=0.007) and ~7 fold (n=3) lower than wild type Samd14 expressing cells, 5 min post SCF stimulation. Relative to Samd14, Samd14∆CPB expression reduced burst forming unit-erythroid (BFU-E) (2.0 fold) and colony forming unit-erythroid (CFU-E) (1.5 fold). These results revealed that the Samd14-CP interaction is a determinant of BFU-E and CFU-E progenitor cell levels and function. Remarkably, as the requirement of the CPB domain in BFU-E and CFU-E progenitors is distinct from the Samd14-SAM domain (which promotes BFU-E but not CFU-E), the function of Samd14 in these two cell types may differ. Ongoing studies will examine whether the function of Samd14 extends beyond SCF/c-Kit signaling and establish cell type-dependent functions of Samd14 and Samd14-interacting proteins. Given the critical importance of c-Kit signaling in hematopoiesis, the role of Samd14 in mediating pathway activation, and our discovery implicating the capping protein complex in erythropoiesis, it is worth considering the pathological implications of this mechanism in acute/chronic anemia and leukemia. Disclosures No relevant conflicts of interest to declare.
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Hewitt, Kyle J. "The Samd14-Capping Protein Complex Controls Cell Signaling in the Erythropoietic Stress Response." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-143020.
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In anemia, restoring homeostatic levels of erythrocytes requires an erythropoietic regenerative response to accelerate red blood cell (RBC) production. Elucidating mechanisms that drive the process of erythropoiesis in the context of regeneration or "stress erythropoiesis" can reveal new strategies for targeting ineffective erythropoiesis. An important component of stress erythropoiesis involves stress-dependent activation of genes/proteins through transcriptional enhancers. We discovered an enhancer in intron 1 of the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene elevates Samd14 expression, facilitates SCF/c-Kit signaling, and is needed for survival in a hemolytic anemia model. However, it is dispensable for erythropoietic development. Our prior work demonstrated that the SAM domain of Samd14 promotes c-Kit-mediated cellular signaling to regulate progenitor function, and this SAM domain has functional attributes unique from those of structurally related SAM domains. Using immunoprecipitation-mass spectrometry, we determined that Samd14 interacts with the Capzβ protein. Capzβ is a component of the actin capping protein (CP) complex, which interact as α- and β heterodimers during actin filament assembly/disassembly. CP exerts diverse functions in cell motility, vesicular transport, cell signaling and cytokinesis. Using a series of Samd14 deletion constructs, we tested whether the Samd14-Capzβ interaction is important for Samd14 promotion of c-Kit signaling in stress erythroid progenitors. Our findings determined that the region of Samd14 required for binding to Capzβ (amino acids 38-54) were required to restore c-Kit signaling. Our ongoing studies are examining whether Samd14-Capzβ is similarly required for colony formation and cell survival of stress erythroid progenitors, and whether additional SAM domain-containing proteins have a similar role in regulating stress erythropoiesis. Understanding the fundamental drivers of regenerative erythropoiesis can lead to new therapeutic strategies and prognostic/diagnostic markers. Disclosures No relevant conflicts of interest to declare.
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Thurner, Lorenz, Klaus-Dieter Preuss, Moritz Bewarder, Maria Kemele, Natalie Fadle, Evi Regitz, Sarah Altmeyer, et al. "Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma." Blood 132, no. 26 (December 27, 2018): 2744–53. http://dx.doi.org/10.1182/blood-2018-03-836932.
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Abstract To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
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Hewitt, Kyle, Kirby D. Johnson, Duk-Hyoung Kim, Prithvia Devadas, Rajalekshmi Prathibha, Chandler Zuo, Colin Dewey, et al. "Cistrome Control of Hematopoieitic Stem/Progenitor Cell Function." Blood 126, no. 23 (December 3, 2015): 43. http://dx.doi.org/10.1182/blood.v126.23.43.43.
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Abstract Cis-regulatory mechanisms control chromatin structure and cellular identity. At the GATA2 locus, two cis-elements are linked to human pathologies, including a primary immunodeficiency (MonoMAC syndrome) associated with multiple complex phenotypes, myelodysplastic syndrome, and acute myeloid leukemia (AML). Mutations that disrupt the function of an intronic GATA2 +9.5 element cause MonoMAC syndrome, while an inversion that relocates the distal GATA2 -77 element to the EVI1 locus induces AML. The +9.5 and -77 cis-elements are GATA-2-occupied and confer context-dependent enhancer activities in select hematopoietic cell types in vivo. In knockout mouse models, the Gata2 +9.5 cis-element is required for hematopoietic stem cell (HSC) genesis, whereas the Gata2 -77 cis-element governs a unique sector of the myeloid progenitor cell transcriptome without impacting HSC genesis. Three other GATA-2-occupied cis-elements (-1.8, -2.8 and -3.9) were not individually required for hematopoietic development, and had relatively mild effects on Gata2 expression; the -1.8 site was required to maintain Gata2 repression in late-stage erythroblasts, the -2.8 conferred maximal Gata2 expression, and the -3.9 had no effect on Gata2 expression. We predict that additional cis-elements exist in the genome with functions resembling the +9.5 and -77, and their analysis will provide important mechanistic and biological insights. We utilized the known properties of Gata2 cis-elements as learning tools to identify prospective constituents of a hematopoietic stem/progenitor cell (HSPC) regulatory cistrome genome-wide. Using sequence attributes shared with the critically-important +9.5 element, namely a CATCTG-8bp spacer-AGATAA, we generated a list of 797 candidate cis-elements ("+9.5-like" elements). This list was prioritized using chromatin occupancy by GATA-2 and Scl/TAL-1, among others, chromatin accessibility, evolutionary conservation, and histone modifications in a multitude of biologically-relevant cell types. Gene editing was used to delete three high-ranked elements (Samd14 +2.5, Bcl2l1 +12.2, and Dapp1 +23.5), revealing their importance for transcriptional activation, GATA-2 occupancy and chromatin accessibility, while deletion of two low-ranked elements (Mrps9 +17.6 and Mgmt +182) had no effect on gene transcription. One such cis-element (Samd14 +2.5) resided in Samd14, a gene with undescribed biological function. Samd14 has a conserved sterile α-motif and coiled-coil domain, and is highly expressed in hematopoietic progenitors and differentiated progeny. Mouse knockout of the Samd14 +2.5 element dramatically lowered expression of Samd14 in hematopoietic progenitors. We conducted loss-of-function analysis to elucidate Samd14 function in lineage-depleted (Lin-) E14.5 fetal liver cells infected with control or Samd14 shRNA-expressing retrovirus. In a CFU assay, Samd14 knockdown reduced BFU-E and CFU-GM colonies 3.4-fold. Early erythroid precursor R1 (CD71low, Ter119-) and R2 (CD71high, Ter119-) cell populations decreased ~2-fold, concomitant with increases in more mature R3 and R4/5 populations (Ter119+). In R1/R2 cells, Samd14 knockdown reduced surface c-Kit expression by 1.6-fold and prevented Stem Cell Factor/c-Kit activation of AKT. Cellular deficits resulting from Samd14 knockdown could be rescued by c-Kit. In -77-/- common myeloid progenitors, Samd14 was ~20-fold downregulated. Thus, the importance of Samd14 and the Samd14 +2.5 element on progenitor function and SCF/c-Kit signaling validates our strategy for identifying cis-elements relevant for hematopoiesis. Our findings demonstrate that +9.5-like elements control cell signaling (Samd14 +2.5) and apoptosis (Bcl2l1 +12.2), and we predict that additional cistrome constituents will control these and other important HSPC processes. I will discuss the mechanistic and biological properties of additional cis-elements analyzed from a cohort of 68 GATA-2-occupied elements and general principles arising from the HSPC cistrome analysis, which provide unique insights into the control of hematopoiesis and GATA-2-linked pathologies. Disclosures No relevant conflicts of interest to declare.
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Thurner, Lorenz, Maria Kemele, Natalie Fadle, Evi Regitz, Patrick Roth, Michael Weller, Monika Szczepanowski, et al. "Postranslationally Modified Proteins in the Central Nervous System (CNS) Are the Dominant Antigenic Target/Stimulus of the B-Cell Receptor (BCR) in Primary CNS Lymphomas (PCNSL) Providing Strong Evidence for the Role of Chronic Autoantigenic Stimulation As an Early Step in the Pathogenesis of Aggressive B-Cell Lymphomas." Blood 124, no. 21 (December 6, 2014): 142. http://dx.doi.org/10.1182/blood.v124.21.142.142.
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Abstract Background: Sequence analyses of variable immunoglobulin gene fragments of PCNSL from immunocompetent patients have shown a VH4-34 restriction raising speculations on a selection/stimulation of a functional BCR by an autoantigen in the central nervous system. The present study focused on the search for these hypothetic autoantigens presumably driving the malignant transformation of B-cells into PCNSL cells by chronic BCR stimulation in immunocompetent patients. Methods: BCRs were expressed as recombinant Fabs based on corresponding pairs of functional variable region heavy and light chain genes, which had been amplified from isolated genomic DNA of snap-frozen lymphoma specimens and checked for binding to proteins expressed on macroarrays of human cDNA expression libraries. Results: Recombinant BCR expression was attempted in 21 and successful in twelve PCNSL cases. The VH4-34 family was overrepresented, but was found in less than a quarter of the PCNSL patients (4/21). Screening of the recombinant BCRs on protein arrays revealed that 8 of 12 recombinant PCNSL-BCRs reacted with SAMD14 and the SAM domain of neurabin-1, two proteins with high homology and preferential expression in the CNS. Subsequent proteomic analysis of cryoconserved lymphoma specimens showed that SAMD14 and the SAM domain of neurabin-1 were alternatively N-glycosylated in patients with a PCNSL-BCR specific for SAMD14 and neurabin-1, but not in the remaining PCNSL patients with BCR specificities other than for SAMD14/neurabin-1. Compared to SAMD14 and neurabin-1 from healthy controls, Asn 339 of SAMD14 and Asn 1277 of neurabin-1 were shown to carry additionally glycosylated Asn residues. Of interest, both additional glycosylation sites belonged to atypical, non-canonical Asn-Leu-Glu-Gln (N-L-E-Q) sites instead of the Asn-X-Ser/Thre consensus sequence (N-X-S/T; where X can be any amino acid except proline), which is reported to constitute 97% of N-glycosylation sites under physiologic circumstances. These atypical N-hyperglycosylations were shown for every case with sufficient biopsy material for this proteomic analysis and a PCNSL-BCR specific for SAMD14 and neurabin-1 in their PCNSL and CNS, and to a lesser degree in their peripheral blood mononuclear cells and patient-derived EBV-transformed lymphoblastoid cell lines (LCLs). Of the recombinant BCRs of all cases with sufficient material to test for hyperglycosylation, only the BCRs of the 6 cases with hyperglycosylated SAMD14/neurabin-1 reacted against SAMD14/neurabin-1. Of note, glycosylation status of 2/8 cases with recombinant SAMD14/neurabin-1 reactive BCRs could not be analyzed due to insufficient cryomaterial left after variable region gene PCRs. No hyperglycosylation of SAMD14 and neurabin-1 was found in the peripheral blood of 400 healthy controls, 100 newborns and 50 nursery residents. Moreover, antibodies against SAMD14 and neurabin-1 were detected in the sera and cerebrospinal fluids of an independent second cohort of patients with PCNSL (8/22), but not in sera of patients with secondary CNS manifestations of systemic DLBCL (0/17) or of healthy controls (0/92). Conclusion: Our results strongly suggest that the atypical (NLEQ) glycosylation of the highly homologous SAMD14 and the SAM domain of neurabin-1 maintains a chronic autoimmunogenic stimulation in the CNS, ultimately leading to the malignant transformation of B-cells with a BCR specific for these atypically N-hyperglycosylated proteins into an aggressive B-cell lymphoma in the CNS in a majority of patients with PCNSL. The fact that the VH4-34 family represents only a minority of VH families recognizing SAMD14/neurabin-1 underlines the extraordinary autoimmunogenicity of these posttranslationally modified proteins in a broad range of individuals. Our results provide the first and strongest experimental evidence for the role of chronic autoantigenic stimulation as a first step in the pathogenesis of aggressive B-cell lymphomas. Supported by Deutsche Forschungsgemeinschaft DFG, Deutsche José Carreras Leukämie Stiftung, Wilhelm-Sander-Stiftung, Deutsche Krebshilfe e.V. Disclosures No relevant conflicts of interest to declare.
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Teng, Linda K. H., Brooke A. Pereira, Shivakumar Keerthikumar, Cheng Huang, Birunthi Niranjan, Sophie N. Lee, Michelle Richards, et al. "Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment." Cancers 13, no. 6 (March 11, 2021): 1237. http://dx.doi.org/10.3390/cancers13061237.
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Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.
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Hewitt, Kyle, Prithvia Devadas, Lily Zemelko, Sunduz Keles, and Emery Bresnick. "SAMD14 enhancer-mediated hematopoietic stress signaling." Experimental Hematology 44, no. 9 (September 2016): S79. http://dx.doi.org/10.1016/j.exphem.2016.06.156.
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Thurner, L., M. Bewarder, N. Fadle, E. Regitz, V. Poeschel, M. Ziepert, R. Schuck, et al. "SAMD14/NEURABIN-I AS BCR-ANTIGENS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA." Hematological Oncology 37 (June 2019): 195–96. http://dx.doi.org/10.1002/hon.9_2630.
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Zhang, Haibin, Cheng Chen, Yinghong Cui, Yuqing Li, Zhaojun Wang, Xinzhan Mao, Pengcheng Dou, Yihan Li, and Chi Ma. "lnc-SAMD14-4 can regulate expression of the COL1A1 and COL1A2 in human chondrocytes." PeerJ 7 (September 2, 2019): e7491. http://dx.doi.org/10.7717/peerj.7491.
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Osteoarthritis (OA) is the most common motor system disease in aging people, characterized by matrix degradation, chondrocyte death, and osteophyte formation. OA etiology is unclear, but long noncoding RNAs (lncRNAs) that participate in numerous pathological and physiological processes may be key regulators in the onset and development of OA. Because profiling of lncRNAs and their biological function in OA is not understood, we measured lncRNA and mRNA expression profiles using high-throughput microarray to study human knee OA. We identified 2,042 lncRNAs and 2,011 mRNAs that were significantly differentially expressed in OA compared to non-OA tissue (>2.0- or < − 2.0-fold change; p < 0.5), including 1,137 lncRNAs that were upregulated and 905 lncRNAs that were downregulated. Also, 1,386 mRNA were upregulated and 625 mRNAs were downregulated. QPCR was used to validate chip results. Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes was used to study the biological function enrichment of differentially expressed mRNA. Additionally, coding-non-coding gene co-expression (CNC) network construction was performed to explore the relevance of dysregulated lncRNAs and mRNAs. Finally, the gain/loss of function experiments of lnc-SAMD14-4 was implemented in IL-1β-treated human chondrocytes. In general, this study provides a preliminary database for further exploring lncRNA-related mechnisms in OA.
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Hewitt, Kyle J., Koichi R. Katsumura, Daniel R. Matson, Prithvia Devadas, Nobuyuki Tanimura, Alexander S. Hebert, Joshua J. Coon, et al. "GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia." Developmental Cell 42, no. 3 (August 2017): 213–25. http://dx.doi.org/10.1016/j.devcel.2017.07.009.
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Xu, Xiaoyang, Xiaojing Chang, Yan Xu, Peng Deng, Jiang Wang, Chundong Zhang, Xinjiang Zhu, Shuchen Chen, and Dongqiu Dai. "SAMD14 promoter methylation is strongly associated with gene expression and poor prognosis in gastric cancer." International Journal of Clinical Oncology 25, no. 6 (March 21, 2020): 1105–14. http://dx.doi.org/10.1007/s10147-020-01647-4.
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Nagata, Yasunobu, Satoshi Narumi, Yihong Guan, Bartlomiej P. Przychodzen, Cassandra M. Hirsch, Hideki Makishima, Hirohito Shima, et al. "Opposing Pathogenesis of Germline SAMD9/SAMD9L Variants in Adult Myelodysplastic Syndrome (MDS)." Blood 132, Supplement 1 (November 29, 2018): 4351. http://dx.doi.org/10.1182/blood-2018-99-119896.
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Abstract Familial myelodysplastic syndromes (MDS), leukemias, and bone marrow failure (BMF) syndromes, typically present in children and young adults. Such cases associate with germ line (GL) mutations in DDX41, RUNX1,ETV6, GATA2 and ANKRD26 and were recently designated by WHO to constitute a separate disease. Gain-of-function (GOF) GL mutations in SAMD9 and SAMD9L associate with familial pediatric myelodysplastic syndrome (MDS) cases that often have early onsets and -7/del(7q). It was not known if this was the case in sporadic adult MDS. With this question in mind, we compiled sequencing results on 799 adults with presumably acquired MDS and BMFs, and further enhanced these results through public WES data on 349 myeloid neoplasms. We also performed cell growth assays of exemplary SAMD9 and SAMD9L GL variants identified in adult MDS. We used Broad Institute's Genome Aggregation Database (gnomAD) as healthy controls (n = 138,632). After comparing ethnicities between gnomAD and our cohort, we matched healthy controls to patients by ethnicities. Defining rare variants as those present in <0.1% of ethnically-matched healthy controls, we found 26 rare SAMD9/SAMD9L GL variants in 3% (24/799) patients. Most were missense; 3 were truncating (nonsense or frameshift All variants were heterozygous except two patients with two variants. We further validated these data were validated in public WES databases. We identified 2% (7/349) of adult MDS patients in public database with GL SAMD9/SAMD9L variants. SAMD9/SAMD9L GL variants were located in the N-terminal significantly more in adult MDS than reported for pediatric MDS [SAMD9; 62% (8/13) vs. 17% (5/30), p=.044, SAMD9L; 62% (7/13) vs. 0% (0/30), p=.0026]. Compared to reported pediatric MDS patients, adult MDS patients had significantly less deletions of chromosome7/del(7q) [8% (2/24) vs. 69% (22/32), p=.0037] and more 5q deletions [33% (8/24) vs. 4% (1/24), p=.022]. Conservative predictions for specific SAMD9 missense variants were made by using SAMD9 GL variants reported in previous papers or public databases of registered healthy donors, and comparing Area Under the Curve of 8 different prediction algorithms. It defined 11 missense variants as "pathogenic". 57% (4/7) of the variants identified in public WES database were also likely pathogenic by our criteria. We evaluated the growth activity of these 11 unique pathogenic missense variants and 1 frameshift variant identified in a patient with -7. Compared to WT-SAMD9, Thr205Pro-SAMD9, Ile247Thr-SAMD9, and Leu574Pro-SAMD9 showed more proliferative cell growth, whereas, I268T-SAMD9 and D550V-SAMD9L had no significant differences compared to the WT. Compared to WT-SAMD9L, 6 variants (Glu220Gly, Leu1323fs, Cys228Tyr, Trp517Arg, Gly235Ser, and Trp333Cys), fused SAMD9L separately, also had higher proliferation rates than WT-SAMD9L. In total, 9 out of 13 variants (69%) cell growth was not suppressed compared to wild-type cells. Pediatric MDS variants showing less cell growth than the wild type cells suggests that they enhance the normal function of SAMD9/SAMD9L, which is to slow cell cycle progression. In this sense they are gain of function mutations (GOF). In contrast, the majority of variants identified in adult MDS were loss-of-function (LOF) mutations. Thus, given the different distribution of variants, lack of genetic reversion, and opposing functional results, we conclude that GL SAMD9/SAMD9L variants might have different consequences in familial childhood vs. adult disease. Sporadic adult MDS patients lacked early onset and genetic reversions following acquisition of -7/del(7q) or another mutations in cis characterized in pediatric MDS patients. SAMD9/SAMD9L variants could have two conflicting consequences; i) GOF mutations in pediatric patients that result in genetic reversion or MDS associated with aberrations of chromosome 7 with an early onset, or ii) LOF variants resulting in a late development of MDS due to haplo-insufficiency of SAMD9/SAMD9L. Our findings suggest that GL SAMD9/SAMD9L variants may be linked to the pathogenesis of a subset of adult sporadic MDS patients. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy.
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Wang, Qiong, Shun’an Xu, Zheyu Wen, Qizhen Liu, Lukuan Huang, Guosheng Shao, Ying Feng, and Xiaoe Yang. "Combined Plant Growth-Promoting Bacteria Inoculants Were More Beneficial than Single Agents for Plant Growth and Cd Phytoextraction of Brassica juncea L. during Field Application." Toxics 10, no. 7 (July 17, 2022): 396. http://dx.doi.org/10.3390/toxics10070396.
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Single or combined plant growth-promoting bacteria (PGPB) strains were widely applied as microbial agents in cadmium (Cd) phytoextraction since they could promote plant growth and facilitate Cd uptake. However, the distinct functional effects between single and combined inoculants have not yet been elucidated. In this study, a field experiment was conducted with single, double and triple inoculants to clarify their divergent impacts on plant growth, Cd uptake and accumulation at different growth stages of Brassica juncea L. by three different PGPB strains (Cupriavidus SaCR1, Burkholdria SaMR10 and Sphingomonas SaMR12). The results show that SaCR1 + SaMR10 + SaMR12 combined inoculants were more effective for growth promotion at the bud stage, flowering stage, and mature stage. Single/combined PGPB agents of SaMR12 and SaMR10 were more efficient for Cd uptake promotion. In addition, SaMR10 + SaMR12 combined the inoculants greatly facilitated Cd uptake and accumulation in shoots, and enhanced the straw Cd extraction rates by 156%. Therefore, it is concluded that the application of PGPB inoculants elevated Cd phytoextraction efficiency, and the combined inoculants were more conductive than single inoculants. These results enriched the existing understanding of PGPB agents and provided technical support for the further exploration of PGPB interacting mechanisms strains on plant growth and Cd phytoextraction, which helped establish an efficient plant–microbe combined phytoremediation system and augment the phytoextraction efficiency in Cd-contaminated farmlands.
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Avedova, A. Ya, I. V. Mersiyanova, A. V. Pavlova, E. R. Sultanova, U. N. Petrova, D. N. Balashov, L. N. Shelikhova, et al. "Clinical characteristics of patients with the SAMD9/SAMD9L gene defects." Pediatric Hematology/Oncology and Immunopathology 21, no. 3 (August 29, 2022): 126–35. http://dx.doi.org/10.24287/1726-1708-2022-21-3-126-135.
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Conditions associated with defects in the SAMD9/SAMD9L genes represent a relatively new group of diseases characterized by a diverse range of clinical manifestations: from multisystem disorders such as MIRAGE syndrome to isolated hematological manifestations. A previous history of infectious diseases in patients with SAMD9/SAMD9L gene defects before the onset of hematological manifestations is in most cases associated with the defects of the immune system. Gain- or change-of-function germline mutations in the SAMD9/SAMD9L genes are the most common predisposition factors for pediatric myelodysplastic syndrome (MDS) with monosomy 7. However, SAMD9/SAMD9L patients with cytogenetic rearrangements but without any signs or symptoms of MDS can have spontaneous remission due to various compensatory cellular mechanisms. The presence of primary immunodeficiency and a predisposition to MDS at an early age requires a more detailed approach to this group of patients and early determination of indications for allogeneic hematopoietic stem cell transplantation. The patients’ parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications.
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Matsui, Hirotaka, Akiko Nagamachi, Yuko Ozaki, Hiroya Asou, Hiroaki Honda, and Toshiya Inaba. "Samd9L-Deficient Mice Develop Myeloid Malignancies Mimicking Human Diseases with Monosomy 7." Blood 118, no. 21 (November 18, 2011): 869. http://dx.doi.org/10.1182/blood.v118.21.869.869.
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Abstract Abstract 869 Monosomy 7 is a common chromosomal abnormality found frequently in MDS and AML. We previously identified a common microdeletion cluster in subband 7q21.3 in JMML patients (Asou et al., 2009). This cluster contains three poorly characterized genes: sterile alpha motif (SAM) domain-9 (Samd9) which is absent in mice, Samd9-like (Samd9L) and Miki (LOC253012). In this study we established and characterized Samd9L-deficient mice in detail and found that these mice develop myeloid malignancies that mimic human diseases with −7/7q-. Samd9L −/− (n=10), Samd9L+/− (n=11) and Samd9L+/+ (n=13) littermates were observed for signs of illness for 2 years. All but one Samd9L+/+ mice maintained consistent WBC counts and hemoglobin levels throughout the observation period. Meanwhile, seven among 21 Samd9L+/− and Samd9L−/− mice developed neutropenia and/or anemia and 2 mice showed an apparent WBC increase after the age of 18 months. Based on Bethesda proposals for classification, the types and frequencies of myeloid diseases demonstrated by mice included myeloid dysplasia (5/10 Samd9L−/−; 2/11 Samd9L+/−), myeloid leukemia (1/10 Samd9L−/−; 1/11 Samd9L+/−) and myeloproliferative disease (1/11 Samd9L+/−). To determine whether loss of the Samd9L gene predisposes mice to myeloid diseases, newborn mice were injected with MOL4070A retrovirus which selectively induces AML or MDS in mice with propensity to myeloid malignancies. There was a significant effect, in that almost all Samd9L+/− (12/14) and Samd9L−/− (10/12) mice died from myeloid neoplasms, roughly one year earlier than mice that developed spontaneous myeloid malignancies without retroviral infection. In contrast, only 2 of 30 MOL4070A-infected Samd9L+/+ mice developed myeloid diseases. Unlike uninfected Samd9L+/− and Samd9L−/− mice, which preferentially developed MDS (7/21), 16 of 26 virus-infected mice showed myeloid leukemias of various subtypes including undifferentiated, myelomonocytic, or monocytic leukemia that expressed combinations of surface markers for the granulocytic, monocytic, erythroid or megakaryocytic lineage. By applying inverse PCR method, two common retrovirus integration sites, Evi1 and Fbxl10 genes, were identified in leukemic samples specifically from Samd9L−/− and Samd9L+/− mice. The enhanced incidence of leukemia in mice with Samd9L-deficiency by Evi1 or Fbxl10 overexpression was further analyzed by transplanting Samd9L−/− or Samd9L+/+ bone marrow cells transduced with retrovirus expressing Evi1 or Fbxl10. All mice (11/11) receiving transferred Samd9L−/−Evi1 bone marrow cells died from hematopoietic malignancies, particularly myeloid disorders (10/11). While not a statistically significant result, we also found that three of 13 mice receiving transferred Samd9L −/−Fbxl10 bone marrow cells developed myeloid malignancies. The development of MDS in Samd9L+/− and Samd9L−/− mice of advancing age mimics the typical clinical association between −7/7q- and sporadic MDS in elderly humans, while development of wide-variety of myeloid leukemia subtypes in retrovirus-infected Samd9L+/− and Samd9L−/− mice indicates that Samd9L gene-deficiency can promote diverse leukemogenic pathways, mimicking another clinical feature of −7/7q-: i.e., deep involvement in therapy-related AML/MDS as well as AML/MDS among patients with a propensity for myeloid diseases. As we reported last year, Samd9L protein localizes to the early endosome. Cells expressing Samd9L at low levels internalize ligand-bound cytokine receptors normally, but there is a delay in homotypic fusion of endosomes that results in prolonged cellular activation to cytokine signals. Moreover, colony replating assay revealed that Samd9L+/− and Samd9L−/− bone marrow cells maintain colony forming ability beyond 7th plating. Although detailed mechanisms remain to be elucidated, we hypothesize that excess cytokine-receptor signaling due to Samd9/Samd9L insufficiency induces self-renewal of hematopoietic stem cells and/or delays in differentiation of early progenitors, resulting in the development of myeloid neoplasms in cooperation with genetic and age-related epigenetic alterations. Disclosures: No relevant conflicts of interest to declare.
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Inaba, Toshiya, Hiroaki Honda, and Hirotaka Matsui. "The enigma of monosomy 7." Blood 131, no. 26 (June 28, 2018): 2891–98. http://dx.doi.org/10.1182/blood-2017-12-822262.
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Abstract Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (−7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. SAMD9 (sterile α motif domain 9) and SAMD9L (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in SAMD9L-deficient mice over their lifetime, SAMD9/SAMD9L are likely responsible for sporadic MDS with −7/del(7q) as the sole anomaly. EZH2 (enhancer of zeste homolog 2) and MLL3 (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to SAMD9/SAMD9L, loss of EZH2 or MLL3 likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of TET2 or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying −7/del(7q).
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Ahn, Jinwoo, Caili Hao, Junpeng Yan, Maria DeLucia, Jennifer Mehrens, Chuanping Wang, Angela M. Gronenborn, and Jacek Skowronski. "HIV/Simian Immunodeficiency Virus (SIV) Accessory Virulence Factor Vpx Loads the Host Cell Restriction Factor SAMHD1 onto the E3 Ubiquitin Ligase Complex CRL4DCAF1." Journal of Biological Chemistry 287, no. 15 (February 23, 2012): 12550–58. http://dx.doi.org/10.1074/jbc.m112.340711.
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The sterile alpha motif and HD domain-containing protein-1 (SAMHD1) inhibits infection of myeloid cells by human and related primate immunodeficiency viruses (HIV and SIV). This potent inhibition is counteracted by the Vpx accessory virulence factor of HIV-2/SIVsm viruses, which targets SAMHD1 for proteasome-dependent degradation, by reprogramming cellular CRL4DCAF1 E3 ubiquitin ligase. However, the precise mechanism of Vpx-dependent recruitment of human SAMHD1 onto the ligase, and the molecular interfaces on the respective molecules have not been defined. Here, we show that human SAMHD1 is recruited to the CRL4DCAF1-Vpx E3 ubiquitin ligase complex by interacting with the DCAF1 substrate receptor subunit in a Vpx-dependent manner. No stable association is detectable with DCAF1 alone. The SAMHD1 determinant for the interaction is a short peptide located distal to the SAMHD1 catalytic domain and requires the presence of Vpx for stable engagement. This peptide is sufficient to confer Vpx-dependent recruitment to CRL4DCAF1 and ubiquitination when fused to heterologous proteins. The precise amino acid sequence of the peptide diverges among SAMHD1 proteins from different vertebrate species, explaining selective down-regulation of human SAMHD1 levels by Vpx. Critical amino acid residues of SAMHD1 and Vpx involved in the DCAF1-Vpx-SAMDH1 interaction were identified by mutagenesis. Our findings show that the N terminus of Vpx, bound to DCAF1, recruits SAMHD1 via its C terminus to CRL4, in a species-specific manner for proteasomal degradation.
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Bluteau, Olivier, Marie Sebert, Thierry Leblanc, Régis Peffault de Latour, Samuel Quentin, Elodie Lainey, Lucie Hernandez, et al. "A landscape of germ line mutations in a cohort of inherited bone marrow failure patients." Blood 131, no. 7 (February 15, 2018): 717–32. http://dx.doi.org/10.1182/blood-2017-09-806489.
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Key Points Next-generation sequencing broadens the spectrum of germ line mutations in a cohort of patients with likely-inherited BMF. Salient clinical features and distinct natural histories are consistently found in SAMD9L and SAMD9, MECOM/EVI1, and ERCC6L2 disorders.
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Schwartz, Jason R., Marcin W. Wlodarski, and Jeffery M. Klco. "Role of Genetic Evolution and Germline Mutations in SAMD9 and SAMD9L Genes." Blood 134, Supplement_1 (November 13, 2019): SCI—33—SCI—33. http://dx.doi.org/10.1182/blood-2019-121042.
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Acquired deletions on chromosome 7 (monosomy 7/del7q) are common in myeloid neoplasms, especially pediatric MDS and AML. Although these tumors have historically been reported to occur within families, suggesting a genetic predisposition, the genetic lesion(s) that initiate these diseases has remained elusive until the last few years. Following a series of publications in which germline mutations in SAMD9 and SAMD9L were reported in a MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively, our group and others described similar heterozygous missense germline mutations in pediatric MDS, especially non-syndromic familial MDS with monosomy 7. Mutations in SAMD9 and SAMD9L have now also been reported in transient monosomy 7, inherited bone marrow failure and AML. Collectively, it is estimated that germline mutations in these genes are present in nearly 20% of children with MDS, with a strong enrichment in those with monosomy 7. Surprisingly, SAMD9 and SAMD9L are paralogous genes adjacently located on human chromosome 7 at band 7q21, and the monosomy 7 clone that expands in children universally lacks the pathologic germline variant. Expression of the mutant proteins in cells results in profound growth suppression, suggesting that there is strong selective pressure for hematopoietic cells to not express the mutant alleles. In addition to chromosome loss, additional methods that suppress expression of the pathologic allele have been described. These include copy neutral loss of heterozygosity (CN-LOH) with duplication of the wild-type allele or the somatic acquisition of additional mutations in cis with the germline mutation that counteract the growth suppressive effect of the germline mutation. The clinical phenotype is largely dictated by the revertant mutation in the dominant hematopoietic clone within the patient's bone marrow. Those with an expansion of a CN-LOH clone are more commonly asymptomatic, in contrast to those patients with a dominant monosomy 7 clone. Progression to higher grade MDS or AML is associated with the acquisition of additional somatic mutations including mutations in SETBP1, KRAS and RUNX1. The recognition of these germline mutations has had an immediate impact on the clinical management of children with MDS, including their family members, and ongoing clinical work in the pediatric MDS community is aimed at establishing guidelines for the pathologic diagnosis, clinical monitoring and treatment for these patients. In addition to these ongoing clinical pursuits, there is significant research interest in these genes, the function of their proteins in hematopoietic cells and how the germline mutations alter the function of the wild-type protein. The SAMD9 and SAMD9L proteins are largely uncharacterized and have been shown to be important in endocytosis, growth factor signaling and to have antiviral properties. Intriguingly, SAMD9 and SAMD9L are both induced by inflammatory signals, including interferons, suggesting a link between inflammatory stress and the disease phenotype. Ongoing studies are aimed at developing models, including in vitro and in vivo models, to understand the mechanisms by which these germline mutations can ultimately lead to the development of pediatric MDS and related disorders. Disclosures No relevant conflicts of interest to declare.
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Matsui, Hirotaka, Akiko Nagamachi, Akinori Kanai, Yuko Ozaki, Hiroaki Honda, and Toshiya Inaba. "Haploinsufficiency Of SAMD9L, An Endosome Fusion Facilitator, In Mice Induces The Development Of Myeloid Malignancies Mimicking Human Diseases With Monosomy 7." Blood 122, no. 21 (November 15, 2013): 227. http://dx.doi.org/10.1182/blood.v122.21.227.227.
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Abstract Monosomy 7 is a common chromosomal abnormality found frequently in MDS and AML. We previously identified a common microdeletion cluster in 7q21.3 in juvenile myelomonocytic leukemia patients. This cluster contains three poorly characterized genes: sterile alpha motif (SAM) domain-9 (SAMD9) which is absent in mice, samd9-like (SAMD9L) and Miki (LOC253012). Although mutations have rarely been seen in these genes, the genes reside proximal to the 7q22 band that is deleted in single copy in nearly 25% of AML and MDS patients. We recently reported that Miki, a centrosomal protein that promotes alignment of chromosomes at metaphase, is a candidate gene responsible for mitotic/nuclear abnormalities observed in MDS patients (Mol Cell 2012). In this study, we established and characterized SAMD9L-deficient mice, along with the analysis of molecular function of SAMD9L protein. Among SAMD9L-/- (n=15) and SAMD9L+/- (n=15) littermates, 13 mice developed myeloid dysplasia, 2 mice developed myeloid leukemia and one mouse developed myeloproliferative disease after the age of 18 months, while all but one SAMD9L+/+ mice (n=23) maintained normal hematopoiesis throughout the 24-month observation period. Infection of MOL4070A retrovirus into newborn mice developed myeloid leukemia within 15 months preferentially in SAMD9L-deficient genetic background with Evi1 and Fbxl10 (encoding a H3K36 demethylase) genes as common virus integration sites. While bone marrow (BM) cells from SAMD9L+/+ mice (12 weeks old) formed fewer colonies by the third replating, cells from SAMD9L-deficient mice continued to form similar numbers and sizes of well-differentiated colonies beyond the 7th plating. The excess number of colonies formed was reduced by retrovirus-mediated forced expression of Samd9L. These data suggested enhanced self-renewal and/or delays in differentiation of SAMD9L-deficient stem cells. In addition, enhanced reconstitution ability of SAMD9L-deficient stem cells was demonstrated by competitive repopulation assay using the Ly5 congenic mouse system, where irradiated Ly5.1 mice were transplanted with long term-LSK cells from SAMD9L+/+ or SAMD9L-deficient Ly5.2 mice (10 weeks old) together with BM cells from SAMD9L+/+Ly5.1 mice. This was confirmed by limiting-dilution transplants, results of which showed a higher frequency of multi-lineage repopulating cells at 8 weeks in SAMD9L-/- donor BM. Moreover, growth advantage in the presence of cytokines was evident in liquid cultures of SAMD9L-deficient BM progenitor cells. Hypersensitivity of SAMD9L-deficient BM progenitors to cytokines was also shown in in vivo experiments, in which SAMD9L-deficient mice injected with cyclophosphamide (day 0) and G-CSF (days 1-4) showed significantly higher WBC counts than SAMD9L+/+ mice at the nadir (day 3). These findings suggested that SAMD9L-deficiency sensitizes hematopoietic progenitors to cytokines. Immunostaining using SAMD9L antibody showed a vesicular pattern of SAMD9L localization in approximately 15% of BM progenitor cells that overlapped with the localization of EEA1, an early endosomal protein. In SAMD9L-/- fibroblasts, while rapid endocytosis of PDGF-receptor (PDGFR) by PDGF stimulation occurred in a time-course similar to that in SAMD9L+/+ cells, homotypic fusion of endosomes containing PDGFR delayed. Inhibition of endosome fusion in SAMD9L-/- cells lead to the accumulation of PDGFR that were remained to be phosphorylated in early endosome, resulting in the prolonged activation of cytokine signals. Accumulation of cytokine receptors in early endosome and persistent cytokine signals were also found in BM progenitors obtained from SAMD9L-deficient mice. These observations suggest that SAMD9L is a crucial component of a protein complex that facilitates the degradation of cytokine receptors through the homotypic fusion of endosomes. Collectively, our study suggests the contribution of haploinsufficiency of SAMD9L to the pathogenesis of myeloid diseases harboring -7/7q- through the prolonged activation of cytokine signals that results in the enhancement of stem cell self-renewal and/or delay in differentiation of early progenitors. Deletion of other haploinsufficient tumor-suppressor genes that reside in 7q would collaborate with the deficiency of SAMD9L for myeloid leukemogenesis. Disclosures: No relevant conflicts of interest to declare.
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Viaene, Angela N., and Brian N. Harding. "The Neuropathology of MIRAGE Syndrome." Journal of Neuropathology & Experimental Neurology 79, no. 4 (February 7, 2020): 458–62. http://dx.doi.org/10.1093/jnen/nlaa009.
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Abstract MIRAGE syndrome is a multisystem disorder characterized by myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Mutations in the sterile alpha motif domain containing 9 (SAMD9) gene which encodes a protein involved in growth factor signal transduction are thought to cause MIRAGE syndrome. SAMD9 mutations lead to an antiproliferative effect resulting in a multisystem growth restriction disorder. Though rare, a few patients with SAMD9 mutations were reported to have hydrocephalus and/or cerebellar hypoplasia on imaging. The neuropathologic features of MIRAGE syndrome have not been previously described. Here, we describe the postmortem neuropathologic examinations of 2 patients with a clinical diagnosis of MIRAGE syndrome and confirmed SAMD9 mutations. Common features included microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications. One of the 2 cases showed marked cerebellar hypoplasia with loss of Purkinje and granule neurons as well as multifocal polymicrogyria and severe white matter volume loss; similar findings were not observed in the second patient. These cases demonstrate the variation in neuropathologic findings in patients with MIRAGE syndrome. Interestingly, the findings are similar to those reported in ataxia-pancytopenia syndrome caused by mutations in SAMD9L, a paralogue of SAMD9.
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Sahoo, Sushree Sangita, Victor Pastor Loyola, Pritam Kumar Panda, Enikoe Amina Szvetnik, Emilia J. Kozyra, Rebecca K. Voss, Dirk Lebrecht, et al. "SAMD9 and SAMD9L Germline Disorders in Patients Enrolled in Studies of the European Working Group of MDS in Childhood (EWOG-MDS): Prevalence, Outcome, Phenotype and Functional Characterisation." Blood 132, Supplement 1 (November 29, 2018): 643. http://dx.doi.org/10.1182/blood-2018-99-118389.
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Abstract Hereditary predisposition has been ever since implicated in the etiology of childhood myelodysplastic syndromes (MDS). Until recently, GATA2 deficiency prevailed as a major germline cause in pediatric primary MDS. In the past 2 years, we and others identified germline mutations in paralogue genes SAMD9 and SAMD9L residing on chromosome 7q21.2 as new systemic diseases with high propensity for MDS with monosomy 7. Although initially, mutations in SAMD9 and SAMD9L genes were associated with MIRAGE and Ataxia-Pancytopenia syndromes, respectively, with recent reports the phenotypes are becoming more intertwined. Nevertheless, the predisposition to MDS with monosomy 7 (-7) remains a common clinical denominator. Both genes are categorized as negative regulators of cellular proliferation and mutations were shown to be activating. Because of their high evolutionary divergence, classical in silico prediction is erratic, thereby establishing in vitro testing as the current gold standard for pathogenicity evaluation. The objectives of this study were to define the prevalence of SAMD9/9L germline mutations in primary pediatric MDS, and to describe the clinical phenotype and outcome. In addition, we aimed to characterize the somatic mutational architecture and develop a functional scoring system. Within the cohort of 548 children and adolescents with primary MDS diagnosed between 1998 and 2016 in Germany, 43 patients (8%) carried SAMD9/9L mutations that were mutually exclusive with GATA2 deficiency and known constitutional bone marrow (BM) failure. MDS type refractory cytopenia of childhood was diagnosed in 91% (39/43), and MDS with excess blasts in 9% (4/43) of mutated cases. Karyotype at diagnosis was normal in 58%, and -7 was detected in 37% of SAMD9/9L cohort. Within MDS subgroup with -7 (n=74), SAMD9/9L mutations accounted for 22% of patients. Notably, the demographics, familial disease, diagnostic blood and BM findings, overall survival (OS) and the outcome after HSCT were not influenced by mutational status in our study cohort (n=548). At the last follow up, 88% (38/43) of SAMD9/9L MDS patients were alive; 35/43 had been transplanted with a 5-year-OS of 85%. Next, we added 26 additional cases with SAMD9/9L mutations diagnosed in Europe within EWOG-MDS studies. In the total cohort of 69 germline mutated patients we found a total of 75 SAMD9/9L mutations, of which 67 were novel. Of those we tested 47 using a HEK293 cell in vitro system and 45/47 mutants inhibited proliferation. While 53/69 patients carried only single germline mutations (missense in 50/53 and truncating in 3/53), in the remaining 16 patients, 11 additional truncating and 7 missense mutations were found. We did not observe an association between germline mutation and phenotype. Immunological issues (e.g. recurring infections, low Ig) were described in 32%/50% of SAMD9/9L-mutated patients, while physical anomalies were very heterogeneous and reported in ~50% of patients in both mutational groups. Intriguingly, genital phenotypes occurred in 40% of SAMD9L, while neurological problems were present in 30% of SAMD9 - mutational subgroups. To elucidate the somatic mutational landscape, we performed whole exome and deep sequencing of 58 SAMD9/9L patients and identified recurrent somatic mutations in known oncogenes that were earlier associated with pediatric MDS: SETBP1 (10%), RUNX1 (7%), ASXL1 (5%), EZH2 (5%), CBL (3%). The identified somatic mutations occurred in association with monosomy 7 background (18/20). Finally, we utilized the results from functional testing of the 47 SAMD9/9L variants as our test cohort to develop combinatorial in silico scoring. The rationale was to decrease the dependency on functional validation. Based on the results of 20 in silico tools we could concatenate a matrix of 5 algorithms to resolve the pathogenicity of >80% of variants. Using this model, all variants predicted as pathogenic showed also growth-restrictive effect in vitro. In summary, pathogenic SAMD9/9L germline mutations account for 8% of primary pediatric MDS and 22% of MDS/-7. The mutations identified are heterogeneous and their effect can be predicted using a combinatorial in silico - in vitro approach. Finally, the clinical outcome and somatic mutational landscape are not influenced by the mutational status. Disclosures Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Lemos de Matos, Ana, Jia Liu, Grant McFadden, and Pedro J. Esteves. "Evolution and divergence of the mammalian SAMD9/SAMD9L gene family." BMC Evolutionary Biology 13, no. 1 (2013): 121. http://dx.doi.org/10.1186/1471-2148-13-121.
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Wang, Juan, Yuan Zhou, Chunyan Gu, Fang Ming, and Ying Zhang. "LncRNA SAMD12-AS1 Suppresses Proliferation and Migration of Hepatocellular Carcinoma via p53 Signaling Pathway." Journal of Oncology 2022 (August 23, 2022): 1–9. http://dx.doi.org/10.1155/2022/9096365.
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Purpose. Assessment of lncRNA SAMD12-AS1 expression in liver cancer tissues and cell lines to investigate the underlying molecular mechanisms that regulate liver cancer cell growth, development, invasion, and migration. Methods. The lncRNA SAMD12-AS1 expression in tumor tissues of 32 liver cancer patients was measured by real-time PCR, and its effect on the clinicopathological manifestations and liver cancer patients’ prognosis was determined. LncRNA SAMD12-AS1 overexpression and knockdown in liver cancer cell lines were established by cell transfection. The effects of lncRNA SAMD12-AS1 knockdown and overexpression on liver cancer cell growth, development, invasion, and migration were determined by MTT, Transwell, and clonogenic assays. Furthermore, its effects on the expression of E-cadherin, vimentin, p53, and p21 in hepatocellular carcinoma cells were determined by Western blot assay. Results. The level of lncRNA SAMD12-AS1 expression in tumor tissues was remarkably higher than that in paracancerous liver tissues ( p < 0.01 ). It was found that the lncRNA SAMD12-AS1 expression was largely correlated with TNM stage of tumor, vascular invasion, and hepatitis B surface (HBs) antigen in liver cancer patients ( p < 0.05 ). Cell function experiments showed that lncRNA SAMD12-AS1 overexpression promoted liver cancer development, migration, and invasion ( p < 0.05 ), while lncRNA SAMD12-AS1 knockdown inhibited the activity of liver cancer cells to invade and migrate ( p < 0.05 ). Western blot analysis showed that overexpression of lncRNA SAMD12-AS1 markedly inhibited p21, p53, and E-cadherin expression and promoted vimentin expression. Conversely, knockdown of lncRNA SAMD12-AS1 significantly promoted p21, p53, and E-cadherin expression and inhibited vimentin expression ( p < 0.05 ). Conclusion. LncRNA SAMD12-AS1 is associated with the TNM stage and vascular invasion of liver cancer. It promotes liver cancer cell development, invasion, and migration by regulating p53 expression. Thus, lncRNA SAMD12-AS1 could be a novel biological target for the treatment of liver cancer.
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Yoshida, Masanori, Felicia Andresen, Hermann Yang, Sara Lewis, Miriam Erlacher, Dirk Lebrecht, Akiko Shimamura, Charlotte M. Niemeyer, Sushree S. Sahoo, and Marcin W. Wlodarski. "Online Platform for SAMD9 and SAMD9L Variant Annotation and Phenotype Correlation." Blood 140, Supplement 1 (November 15, 2022): 5816–17. http://dx.doi.org/10.1182/blood-2022-166742.
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Simon, Clara, Bastian Stielow, Andrea Nist, Iris Rohner, Lisa Marie Weber, Merle Geller, Sabrina Fischer, Thorsten Stiewe, and Robert Liefke. "The CpG Island-Binding Protein SAMD1 Contributes to an Unfavorable Gene Signature in HepG2 Hepatocellular Carcinoma Cells." Biology 11, no. 4 (April 6, 2022): 557. http://dx.doi.org/10.3390/biology11040557.
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The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-Seq. SAMD1 targets several thousand gene promoters, where it acts predominantly as a transcriptional repressor. HepG2 cells with SAMD1 deletion showed slightly reduced proliferation, but strongly impaired clonogenicity. This phenotype was accompanied by the decreased expression of pro-proliferative genes, including MYC target genes. Consistently, we observed a decrease in the active H3K4me2 histone mark at most promoters, irrespective of SAMD1 binding. Conversely, we noticed an increase in interferon response pathways and a gain of H3K4me2 at a subset of enhancers that were enriched for IFN-stimulated response elements (ISREs). We identified key transcription factor genes, such as IRF1, STAT2, and FOSL2, that were directly repressed by SAMD1. Moreover, SAMD1 deletion also led to the derepression of the PI3K-inhibitor PIK3IP1, contributing to diminished mTOR signaling and ribosome biogenesis pathways. Our work suggests that SAMD1 is involved in establishing a pro-proliferative setting in hepatocellular carcinoma cells. Inhibiting SAMD1’s function in liver cancer cells may therefore lead to a more favorable gene signature.
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Davidsson, Josef, Andreas Puschmann, Ulf Tedgård, David Bryder, Lars Nilsson, and Jörg Cammenga. "SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies." Leukemia 32, no. 5 (February 25, 2018): 1106–15. http://dx.doi.org/10.1038/s41375-018-0074-4.
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Nagata, Yasunobu, Satoshi Narumi, Yihong Guan, Bartlomiej P. Przychodzen, Cassandra M. Hirsch, Hideki Makishima, Hirohito Shima, et al. "Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes." Blood 132, no. 21 (November 22, 2018): 2309–13. http://dx.doi.org/10.1182/blood-2017-05-787390.
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Ahmed, Ibrahim A., Midhat S. Farooqi, Mark T. Vander Lugt, Jessica Boklan, Melissa Rose, Erika D. Friehling, Brandon Triplett, et al. "Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations." Biology of Blood and Marrow Transplantation 25, no. 11 (November 2019): 2186–96. http://dx.doi.org/10.1016/j.bbmt.2019.07.007.
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Sahoo, Sushree S., Victor B. Pastor, Charnise Goodings, Rebecca K. Voss, Emilia J. Kozyra, Amina Szvetnik, Peter Noellke, et al. "Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes." Nature Medicine 27, no. 10 (October 2021): 1806–17. http://dx.doi.org/10.1038/s41591-021-01511-6.
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Martin-Gayo, Enrique, Taylor Hickman, Dina Pimenova, Florencia Pereyra, Eric Rosenberg, Mathias Lichterfeld, and Xu Yu. "Cell-intrinsic HIV-1 immune responses in conventional dendritic cells from HIV-1 elite controllers (P6171)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 118.9. http://dx.doi.org/10.4049/jimmunol.190.supp.118.9.
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Abstract Introduction: Recent data suggest that in most HIV-1-infected individuals, cell-intrinsic immune responses of conventional dendritic cells (cDC) are blocked by the host proteins Samhd1 and Trex1. Elite controllers (EC) control HIV-1 replication in the absence of treatment, but immune defense mechanisms in these patients are not well understood. Here, we investigated cell-intrinsic immune responses to HIV-1 in these specific patients. Methods: PBMC from EC, untreated chronic progressors (CP), HAART-treated and HIV-1 negative subjects were ex vivo infected with HIV-1. Expression of viral replication products, type I interferons, Samhd1 and Trex1 were analyzed by qPCR. Results: cDC from HIV-1 negative persons were moderately susceptible to HIV-1, while cDC from EC and CP supported HIV-1 replication very weakly. However, in CP, HIV-1 replication was blocked at the level of early reverse transcription, likely as a result of high-level Samdh1 expression, while In EC, reverse transcription was unaltered, and restriction of viral replication mostly occurred at the level of integration. Functionally, these altered patterns of viral restriction in cDC from EC were associated with increased cellular activation, secretion of type I interferons and improved abilities to prime T cell responses. Conclusion: cDC from EC can mount cell-intrinsic immune responses against HIV-1, which may support the generation of highly effective HIV-1-specific T cell responses in these patients.
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Uemura, Takeshi, Shunsuke Fujii, Hiroki Yamazaki, Tetsuji Itoh, Kouji Masumoto, and Seiichi Nishizawa. "Development of Small-sized Lysine Enzyme Sensor for Clinical Use." Sensors and Materials 34, no. 8 (August 15, 2022): 3173. http://dx.doi.org/10.18494/sam3914.
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Yang, Yuchun, Zhi-Hong Lin, Chao-Ming Hsu, and Cheng-Fu Yang. "Effect of Temperature Field on Deformation of 3D-Printed Polylactic Acid Objects under Forced Convection." Sensors and Materials 34, no. 5 (May 10, 2022): 1675. http://dx.doi.org/10.18494/sam3814.
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Kim, Dokyun, Mingyun Jang, Kirim Lee, and Wonhee Lee. "Application of Shadow Matching Technique to Improve Smartphone-based Global Navigation Satellite System Positioning Accuracy." Sensors and Materials 34, no. 1 (January 31, 2022): 383. http://dx.doi.org/10.18494/sam3714.
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Shu, Qi Qian,Liang, Linghao Wang, and Zhizhou Bao. "Multi-objective Optimization of Non-invasive Voltage Sensor Considering Sensitivity, Array Arrangement, and Cost." Sensors and Materials 34, no. 11 (November 8, 2022): 3967. http://dx.doi.org/10.18494/sam4104.
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Ichikawa, Kenta, and Wataru Hijikata. "Novel Self-powered Flexible Thin Bite Force Sensor with Electret and Dielectric Elastomer." Sensors and Materials 34, no. 11 (November 30, 2022): 4237. http://dx.doi.org/10.18494/sam4134.
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Cho, Hyun-Min, Jae-Heun Oh, Jin-Woo Park, Yun-Sung Choi, Jung-Soo Lee, and Sang-Kyun Han. "Application of Real-time Positioning Systems to a Forest Stand for Precision Forest Management." Sensors and Materials 34, no. 12 (December 26, 2022): 4651. http://dx.doi.org/10.18494/sam4214.
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Oh, Haeng Yeol, and Meong-Hun Jeong. "Grid-based Urban Fire Prediction Using Extreme Gradient Boosting (XGBoost)." Sensors and Materials 34, no. 12 (December 28, 2022): 4879. http://dx.doi.org/10.18494/sam4194.
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Morita, Akemi, Dilber Abdireyim, Mieko Kimura, and Yoshinori Itokawa. "The Effect of Aging on the Mineral Status of Female SAMP1 and SAMR1." Biological Trace Element Research 80, no. 1 (2001): 53–65. http://dx.doi.org/10.1385/bter:80:1:53.
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DA'DARA, Akram A., Kimberly HENKLE-DÜHRSEN, and Rolf D. WALTER. "A novel trans-spliced mRNA from Onchocerca volvulus encodes a functional S-adenosylmethionine decarboxylase." Biochemical Journal 320, no. 2 (December 1, 1996): 519–30. http://dx.doi.org/10.1042/bj3200519.
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Complete cDNA and genomic sequences encoding the Onchocerca volvulus S-adenosylmethionine decarboxylase (SAMDC), a key enzyme in polyamine biosynthesis, have been isolated and characterized. The deduced amino acid sequence encodes a 42 kDa proenzyme with a moderate level of sequence homology to eukaryotic SAMDCs. Enzymically active O. volvulusSAMDC was expressed at a high level in an Escherichia colimutant strain lacking endogenous SAMDC. The recombinant enzyme was purified to homogeneity using DEAE-cellulose, methylglyoxal bis(guanylhydrazone)–Sepharose and Superdex S-200 chromatography. It was determined that the recombinant proenzyme is cleaved to produce 32 and 10 kDa subunits. The sequence of the N-terminal portion of the large subunit was determined and comparison with the sequence of the proenzyme revealed that the precise cleavage site lies between Glu86 and Ser87. Gel-filtration experiments demonstrated that these two subunits combine to form an active heterotetramer. Comparison of the cDNA and genomic sequences revealed that the SAMDC mRNA undergoes both cis- and trans-splicing in its 5´-untranslated region (UTR). Anchored PCR on O. volvulusmRNA confirmed the cDNA sequence and identified two distinct trans-spliced products, a 22-nucleotide spliced-leader sequence and a 138 bp sequence containing the 22 nucleotide spliced-leader sequence. Genomic Southern-blot analysis suggests that the O. volvulusSAMDC is encoded by a single-copy gene. This gene spans 5.3 kb and is comprised of nine exons and eight introns. The first intron is located in the 5´-UTR and processing of this intron has a potential regulatory function. The 5´-flanking region of the gene contains potential transcriptional regulatory elements such as a TATA box, two CAAT boxes and AP-1-, C/EBP-, ELP-, H-APF-1-, HNF-5- and PEA3-binding sites.
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Sahoo, Sushree S., Victor B. Pastor, Charnise Goodings, Rebecca K. Voss, Emilia J. Kozyra, Amina Szvetnik, Peter Noellke, et al. "Publisher Correction: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes." Nature Medicine 27, no. 12 (November 19, 2021): 2248. http://dx.doi.org/10.1038/s41591-021-01632-y.
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Mizuguchi, Takeshi, Tomoko Toyota, Satoko Miyatake, Satomi Mitsuhashi, Hiroshi Doi, Yosuke Kudo, Hitaru Kishida, et al. "Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment." Brain 144, no. 4 (April 1, 2021): 1103–17. http://dx.doi.org/10.1093/brain/awab021.
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Abstract A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype–phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype–phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.
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Unno, Keiko, Yoshiichi Takagi, Tomokazu Konishi, Mitsuhiro Suzuki, Akiyuki Miyake, Takumi Kurotaki, Tadashi Hase, et al. "Mutation in Sodium-Glucose Cotransporter 2 Results in Down-Regulation of Amyloid Beta (A4) Precursor-Like Protein 1 in Young Age, Which May Lead to Poor Memory Retention in Old Age." International Journal of Molecular Sciences 21, no. 15 (August 4, 2020): 5579. http://dx.doi.org/10.3390/ijms21155579.
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Senescence-accelerated mouse prone 10 (SAMP10) exhibits cerebral atrophy and depression-like behavior. A line of SAMP10 with spontaneous mutation in the Slc5a2 gene encoding the sodium-glucose cotransporter (SGLT) 2 was named SAMP10/TaSlc-Slc5a2slc (SAMP10-ΔSglt2) and was identified as a renal diabetes model. In contrast, a line of SAMP10 with no mutation in SGLT2 (SAMP10/TaIdrSlc, SAMP10(+)) was recently established under a specific pathogen-free condition. Here, we examined the mutation effect in SGLT2 on brain function and longevity. No differences were found in the survival curve, depression-like behavior, and age-related brain atrophy between SAMP10-ΔSglt2 and SAMP10(+). However, memory retention was lower in SAMP10-ΔSglt2 mice than SAMP10(+). Amyloid beta (A4) precursor-like protein 1 (Aplp1) expression was significantly lower in the hippocampus of SAMP10-ΔSGLT2 than in SAMP10(+) at 2 months of age, but was similar at 12 months of age. CaM kinase-like vesicle association (Camkv) expression was remarkably lower in SAMP10(+). These genes have been reported to be involved in dendrite function. Amyloid precursor proteins have been reported to involve in maintaining homeostasis of glucose and insulin. These results suggest that mutation in SGLT2 results in down-regulation of Aplp1 in young age, which can lead to poor memory retention in old age.
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Chen, Shuliang, Serena Bonifati, Zhihua Qin, Corine St. Gelais, Karthik M. Kodigepalli, Bradley S. Barrett, Sun Hee Kim, et al. "SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways." Proceedings of the National Academy of Sciences 115, no. 16 (April 2, 2018): E3798—E3807. http://dx.doi.org/10.1073/pnas.1801213115.
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Sterile alpha motif and HD-domain–containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-κB (NF-κB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-κB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-κB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-κB activation by interacting with NF-κB1/2 and reducing phosphorylation of the NF-κB inhibitory protein IκBα. SAMHD1 also interacts with the inhibitor-κB kinase ε (IKKε) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKε-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-κB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-κB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.
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Kokaraki, Georgia, Ioanna Xagoraris, Pedro Farrajota Neves Da Silva, Lesley Ann Sutton, Raul Maia Falcão, Jorge Estefano Santana de Souza, Anders Österborg, Valtteri Wirta, Richard Rosenquist Brandell, and Georgios Z. Rassidakis. "Mutations of the Novel Tumor Suppressor Gene SAMHD1 Are Frequent and Correlate with Decreased Protein Expression in Peripheral T-Cell Lymphomas (PTCL)." Blood 138, Supplement 1 (November 5, 2021): 3515. http://dx.doi.org/10.1182/blood-2021-147428.
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Abstract Introduction: The SAM domain and HD domain 1 (SAMHD1) protein is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, which depletes the intracellular dNTP substrates and thus protects the host (human) cells from replication of viruses such as HIV. Mutations of SAMHD1 gene have been linked to Aicardi-Goutières syndrome (AGS). In lymphoid malignancies, SAMHD1 gene mutations have been detected in a subset of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) resulting in decreased SAMHD1 mRNA levels and also mantle cell lymphoma (MCL) among B-cell neoplasms as well as in a subset (20%) of T-prolymphocytic leukemia (T-PLL). Therefore, SAMHD1 may play a role in oncogenesis as a tumor suppressor. In addition, SAMHD1 may confer resistance to cytarabine by hydrolysing their active triphosphate metabolites and its high protein levels correlate with poorer clinical outcome in acute myeloid leukemia. The mutation status of SAMHD1 gene and its expression patterns in peripheral T-cell lymphoma types is not known yet. The purpose of this study was to investigate SAMHD1 gene alterations using next generation sequencing and SAMHD1 protein expression in common types of PTCL. Methods: The study group included 81 adult patients with peripheral T-cell lymphomas (PTCL) including 26 patients with ALK+ anaplastic large cell lymphoma (ALCL), 20 ALK- ALCL, 13 angioimmunoblastic T-cell lymphomas (AILT) and 22 PTCL, not otherwise specified (NOS) with pre-treatment, formalin-fixed, paraffin-embedded (FFPE) tumor tissues available for immunohistochemical analysis. Double immunostaining (SAMHD1/CD68) was used to distinguish CD68+ histiocytes from the neoplastic T-cells. The Ventana autostainer and a previously validated monoclonal antibody for SAMHD1 (#A303-691A; Bethyl Laboratories, San Antonio, TX, USA) was utilized. The percentage of SAMHD1-positive cells was calculated by counting at least 500 tumor cells in each case. In a subset of 28 PTCLs, next generation sequencing (NGS) was performed using FFPE tissues and an enriched custom TruSight gene panel of 52 genes relevant to lymphoma biology. In addition, 3 control tissue samples were included in the analysis. The analysis pipeline was based on GATK best practices guidelines and all variants were annotated using Ensembl VEP v94.5. Freedom from progression (FFP) and overall survival (OS), were the clinical endpoints. Survival analyses were performed using the Kaplan-Meier method (log-rank test). Results: The expression level of SAMHD1 (percentage of positive neoplastic T-cells) varied significantly with AILT showing the highest level (median percentage 80%) as compared to ALK+ ALCL that showed the lowest level (median percentage 40%) of SAMHD1 expression (p=0.019, Kruskall-Wallis test). SAMHD1 mutations were detected for the first time in a subset of PTCL including 4/11 (36%) ALK+ ALCL, 1/5 (20%) ALK- ALCL, 3/6 (50%) AILT and 2/5 (40%) PTCL, NOS. The SAMHD1 gene alterations included missense mutations, nonsense (stopcodon) and splice region mutations. Importantly, reduced level (low percentage of positive tumor cells) of SAMHD1 protein expression was significantly associated with the presence of SAMHD1 mutations. More specifically, the median percentage of SAMHD1+ neoplastic T-cells was 80% in the PTCL group with wild-type SAMHD1 gene compared to 30% in the PTCL group with mutated SAMHD1 gene (p=0.01, Mann-Whitney U test), thus suggesting that alterations of SAMHD1 gene may represent a mechanism of SAMHD1 protein downregulation in a subset of PTCL. SAMHD1 expression or gene alterations did not correlate with FFP or OS in any PTCL histologic type, although the number of patients included in each group was not adequate to draw definite conclusions for prognostic significance. Conclusions: SAMHD1 gene mutations are frequently detected in a subset of PTCL and are associated with reduced expression of SAMHD1 protein. These findings reveal a novel mechanism (SAMHD1 mutations) of SAMHD1 downregulation in PTCL, and further support the tumor suppressor function of SAMHD1 gene in lymphomas. Disclosures Rosenquist Brandell: AbbVie: Honoraria; AstraZeneca: Honoraria; Illumina: Honoraria; Janssen: Honoraria; Roche: Honoraria.
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Sahoo, Sushree S., Emilia J. Kozyra, and Marcin W. Wlodarski. "Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes." Best Practice & Research Clinical Haematology 33, no. 3 (September 2020): 101197. http://dx.doi.org/10.1016/j.beha.2020.101197.
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Nowacka, Marta, Barbara Ginter-Matuszewska, Monika Świerczewska, Michał Nowicki, Maciej Zabel, Karolina Sterzyńska, and Radosław Januchowski. "The significance of HERC5, IFIH1, SAMD4, SEMA3A and MCTP1 genes expression in resistance to cytotoxic drugs in ovarian cancer cell lines." Medical Journal of Cell Biology 9, no. 3 (September 1, 2021): 138–47. http://dx.doi.org/10.2478/acb-2021-0019.
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Abstract Resistance to chemotherapy is the main obstacle in contemporary ovarian cancer treatment. The aim of this study was the evaluation of expression of HERC5, IFIH1, SAMD4, MCTP1 and SEMA3A mRNA and assessment their role in resistance to cisplatin, paclitaxel, doxorubicin and topotecan in seven ovarian cancer cell lines. MTT assay was used in resistance assessment. Quantitative polymerase chain reaction was performed to measure the expression levels of the genes. We observed different levels of resistance among cell lines. The resistance was not related to the expression of drug transporters genes. The expression of HERC5 and IFIH1 genes was upregulated, and the expression of SEMA3A gene was downregulated. Expression of SAMD4 was upregulated in PEA1, PEA2, and PEO23 cell lines, and expression of MCTP1 was downregulated in A2780, PEA2, and PEO23 cell lines. Upregulation of HERC5, IFIH1, and SAMD4 and downregulation of SEMA3A and MCTP1 in TOP-resistant ovarian cancer cell lines may suggest some role of those genes in topotecan resistance development.
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Plitnik, Timothy, Mark E. Sharkey, Bijan Mahboubi, Baek Kim, and Mario Stevenson. "Incomplete Suppression of HIV-1 by SAMHD1 Permits Efficient Macrophage Infection." Pathogens and Immunity 3, no. 2 (December 6, 2018): 197. http://dx.doi.org/10.20411/pai.v3i2.263.
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Background: Sterile alpha motif and histidine/aspartic acid domain-containing protein (SAMHD1) is a dNTP triphosphorylase that reduces cellular dNTP levels in non-dividing cells, such as macrophages. Since dNTPs are required for reverse transcription, HIV-2 and most SIVs encode a Vpx protein that promotes proteasomal degradation of SAMHD1. It is unclear how HIV-1, which does not appear to harbor a SAMHD1 escape mechanism, is able to infect macrophages in the face of SAMHD1 restriction.Methods: To assess whether HIV-1 had a mechanism to negate SAMHD1 activity, we compared SAMHD1 and dNTP levels in macrophages infected by HIV-1 and SIV. We examined whether macrophages infected by HIV-1 still harbored antiviral levels of SAMHD1 by assessing their susceptibility to superinfection by vpx-deleted SIV. Finally, to assess whether HIV-1 reverse transcriptase (RT) has adapted to a low dNTP environment, we evaluated SAMHD1 sensitivity of chimeric HIV-1 and SIV variants in which the RT regions were functionally exchanged.Results: Here, we demonstrate that HIV-1 efficiently infects macrophages without modulating SAMHD1 activity or cellular dNTP levels, and that macrophages permissive to HIV-1 infection remained refractory to superinfection by vpx-deleted SIV. Furthermore, through the use of chimeric HIV/SIV, we demonstrate that the differential sensitivity of HIV-1 and SIV to SAMHD1 restriction is not dictated by RT.Conclusions: Our study reveals fundamental differences between HIV-1 and SIV in the strategy used to evade restriction by SAMHD1 and suggests a degree of resistance of HIV-1 to the antiviral environment created by SAMHD1. Understanding how these cellular restrictions antagonize viral replication will be important for the design of novel antiviral strategies.Keywords: HIV-1/ macrophages/ SAMHD1