bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulated expression and function of CD122 (interleukin-2/interleukin- 15R-beta) during lymphoid development
Authors: Reya T , Yang-Snyder JA , Rothenberg EV , Carding SR 
Published: October 2019

Abstract
To determine whether signaling via CD122 (interleukin-2 [IL-2]/IL-15 receptor beta-chain) plays a role in regulating the expansion and differentiation of lymphocyte precursors, we have characterized its expression and evaluated its ability to influence the activity of developing lymphoid cells. A significant fraction of Sca1+Lin- hematopoietic stem cells in day 12 fetal liver were found to be CD122+. CD122-mRNA+ and IL-2-mRNA+ cells were also localized in embryo sections within pharyngeal blood vessels adjacent to and surrounding the thymic analgen. This distribution is consistent with the migration of CD122+ progenitor cells from the liver to the developing thymus where a majority of Sca1+ intrathymic T-cell progenitors were CD122+. Analysis of CD122 expression in the day 12 fetal liver revealed that the majority of B220+ cells were CD122+. Furthermore, CD122 expression was restricted to the earliest B220+ cells (CD43+CD24-; prepro B cells; fraction A) that proliferate vigorously to IL-2 in the absence of any stromal cells, but not to IL-15. Consistent with a role for the IL-2/IL- 2R pathway in lymphocyte development is the progressive loss of B cells seen in IL-2-deficient mice. Together, these observations suggest that CD122 plays a role in regulating normal lymphocyte development in vivo.
The BCR-ABL oncogene requires both kinase activity and src-homology 2 domain to induce cytokine secretion
Authors: Anderson SM , Mladenovic J 
Published: October 2019

Abstract
Expression of either the BCR-ABL or the v-abl oncogene in the factor- dependent murine myeloid cell line FDCP-1 results in growth factor independence. Studies with temperature-sensitive mutants of v-abl show that this growth factor independence is oncogene dependent. Likewise, cells expressing a kinase inactive mutant of BCR-ABL did not grow in the absence of interleukin-3 (IL-3). Conditioned media from cells expressing either v-abl or BCR-ABL contained growth factor(s) capable of stimulating the proliferation of uninfected FDCP-1 cells. Based on enzyme-linked immunosorbent assay studies and antibody neutralization studies, the major growth factor present in these conditioned media is IL-3. Because of the importance of SH2 domains in regulating substrate interactions, we examined the ability of SH2 deletion mutants in BCR- ABL to induce growth factor independence. Cells expressing a mutant of BCR-ABL lacking the SH2 domain were growth factor independent; however, they did not secrete growth factors. This finding suggests that while IL-3 produced by cells infected with BCR-ABL may contribute to autocrine or paracrine growth factor independence, expression of an activated tyrosine kinase alone may be able to induce growth factor independence. Furthermore, the secretion of cytokines maybe correlated with a specific region of the BCR-ABL oncogene, suggesting that activation (phosphorylation) of specific substrates may be critical for transcriptional activation of cytokine genes.
High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia [see comments]
Authors: Douer D , Preston-Martin S , Chang E , Nichols PW , Watkins KJ , Levine AM 
Published: October 2019

Abstract
A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).
Distinct temporal patterns of defensin mRNA regulation during drug- induced differentiation of human myeloid leukemia cells
Authors: Herwig S , Su Q , Zhang W , Ma Y , Tempst P 
Published: October 2019

Abstract
Defensins are microbicidal peptides and the principal constituents of neutrophil primary granules. They are presumed to play a prominent role in innate host defenses. We examined defensin mRNA levels during drug-induced differentiation of the promyelocytic leukemia cell line, HL-60. Transcription was restricted to promyelocyte, myelocyte, and very early metamyelocyte stages of the granulocytic pathway. Complete downregulation occurred during late granulocytic maturation or early during phorbol ester-promoted differentiation along the monocyte/macrophage lineage. Retinoic acid (RA) was the strongest inducer of defensin mRNA accumulation, even at doses too low to effect morphologic changes; the initial (first 48 hours), gradual increase resulted from transcriptional activation and was enhanced by granulocyte colony-stimulating factor. In contrast, addition of hybrid polar compounds led to a transient, drug-specific downregulation within the same time period, apparently by means of selectively induced, biphasic degradation of transcripts. Subsequent increase in transcript levels was faster and more pronounced with hexamethylene bisacetamide, relative to dimethyl sulfoxide (DMSO). DMSO-promoted effects were strikingly different in serum-free medium or in the presence of the tyrosine kinase inhibitor, genistein. Under these conditions, and although differentiation was unaffected, early defensin mRNA downregulation was final. The effect did not occur with RA and expression of other myeloid-specific genes was also unchanged. Addition of selected cytokines caused a similar “dip,” only at earlier times and uncoupled from differentiation. Tumor necrosis factor-alpha markedly induced defensin levels after 2 days in previously untreated HL-60 cells, but inhibited expression in RA-differentiated cells. These results begin to detail a complex regulation of defensin mRNA synthesis with both spatial and temporal control elements, and a unique modulation by chemical agents, cytokines, and serum-factors.
Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients
Authors: Deeg HJ , Socie G , Schoch G , Henry-Amar M , Witherspoon RP , Devergie A , Sullivan KM , Gluckman E , Storb R 
Published: October 2019

Abstract
Risk factors for the development of a new (secondary) malignancy after marrow transplantation are still incompletely defined. In the present study, we analyzed results in 700 patients with severe aplastic anemia treated with allogeneic marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle, WA, or at the Hopital St Louis in Paris, France. Twenty-three patients developed a malignancy 1.4 to 221 months (median, 91 months) after transplantation for a Kaplan-Meier estimate of 14% (95% confidence interval, 4% to 24%) at 20 years. Five cases were lymphoid malignancies (two acute lymphoblastic leukemias and three lymphoproliferative disorders) occurring 1.4 to 14.6 months (median, 3 months) posttransplant, and 18 were solid tumors (17 squamous cell and one mucoepidermoid carcinoma) presenting 30 to 221 months (median, 99 months) posttransplant. Thus, the hazard for lymphoid malignancies declined rapidly posttransplant, while the hazard for solid tumors increased progressively with time posttransplant. Risk factors for solid tumors identified in univariable analysis included the underlying diagnosis of Fanconi anemia (P = .0002), azathioprine therapy for chronic graft-versus-host disease (GVHD) (P < .0001), irradiation (total body or thoracoabdominal) as part of the conditioning regimen (P = .0002), chronic GVHD (P = .0099), acute GVHD (P = .0135), and male sex (P = .0499). In multivariable, stepwise proportional hazards models, azathioprine therapy (P < .0001) and the diagnosis of Fanconi anemia (P < .0001) were significant factors for all patients. Irradiation was a significant factor (P = .004) only if the time-dependent variable azathioprine was not included in the analysis. If only non-Fanconi patients were considered, azathioprine (P = .0043), age (P = .025), and irradiation (P = .042) were significant factors. Results in patients with Fanconi anemia and malignancies other than solid tumors were not subjected to an analysis because of the small number of events. It is of note, however, that no case of myeloproliferative disorder was observed. In summary, the highest risk of developing a solid tumor was associated with the diagnosis of Fanconi anemia. Better prevention of GVHD or omission of azathioprine as GVHD therapy (or both) may reduce the risk of late tumor development. Similarly, nonirradiation conditioning regimens may reduce the tumor risk, at least in patients without Fanconi anemia. Interactions between potential risk factors are complex, and further observation and additional analyses will be of interest.
Aorta-associated CD34+ hematopoietic cells in the early human embryo
Authors: Tavian M , Coulombel L , Luton D , Clemente HS , Dieterlen-Lievre F , Peault B 
Published: October 2019

Abstract
Hematopoiesis is established from circulating blood stem cells that seed the embryonic rudiments of blood-forming tissues, a basic notion in developmental hematology. However, the assumption that these stem cells originate from the extraembryonic mesoderm, where primitive hematopoiesis is initiated by intrinsic precursors, has been reconsidered after analysis of blood cell development in avian embryo chimeras: yolk-sac-derived stem cells do not contribute significantly to the definitive blood system, whose first forerunners develop independently along the ventral aspect of the embryonic aorta. Recently, the homologous intraembryonic tissues of the mouse have been submitted to sensitive in vivo and in vitro assays, which showed that they also harbor multipotential hematopoietic stem cells. We have now identified a dense population of hematogenous cells, marked by the surface expression of the CD34 glycoprotein, associated with the ventral endothelium of the aorta in the 5-week human embryo. Therefore, we extend to the human species the growing evidence that intraembryonic hematopoietic cells developing independently of the yolk sac might be the real stem of the whole blood system.
A bicistronic therapeutic retroviral vector enables sorting of transduced CD34+ cells and corrects the enzyme deficiency in cells from Gaucher patients
Authors: Medin JA , Migita M , Pawliuk R , Jacobson S , Amiri M , Kluepfel-Stahl S , Brady RO , Humphries RK , Karlsson S 
Published: October 2019

Abstract
Corrective gene transfer for therapeutic intervention in metabolic and hematopoietic disorders has been hampered by the relatively inefficient transduction of human hematopoietic stem cells. To overcome this, a bicistronic recombinant retrovirus has been generated that delivers both a therapeutic glucocerebrosidase (GC) cDNA for the treatment of Gaucher disease, and a small murine cell surface antigen (heat-stable antigen [HSA]) as a selectable marker. An amphotropic retroviral- producing cell clone was created, and filtered supernatant was used to transduce NIH 3T3 cells. Sorting of transduced cells by flow cytometry enabled separation into populations based on cell surface fluorescence intensity derived from the expressed HSA. Significant increases in GC enzyme activity were seen for the transduced and especially the transduced and sorted cells. Similarly, increases in GC specific activity were seen in transduced and sorted skin fibroblasts from a patient with Gaucher disease. To streamline future transfer and sorting protocols for hematopoietic cells, transformed B-cell lines from Gaucher patients were created. Type I B cells were transduced and sorted, and large increases in GC specific activity occurred with concomitant increases in integrated retroviral copy numbers. In addition, toward the goal of using this selectable approach for corrective gene transfer to bone marrow stem cells, CD34+ cells were isolated from normal BM donors, transduced, and sorted based on cell surface expression of HSA. Proviral DNA was detected in approximately 40% of clonogenic progenitor colonies derived from unsorted, transduced CD34+ cells, demonstrating the high titer of the vector. However, after sorting, 100% of the colonies had the corrective GC cDNA, demonstrating the efficiency of this selective system for human hematopoietic progenitors. It is expected that strategies based on this approach will allow sorting of transduced cells of many types before implantation of transduced cells to animals or patients. This vector system may also be used to simplify manipulations and studies on retroviral-mediated gene delivery in vitro and for in vivo models.
Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis
Authors: Lowell CA , Niwa M , Soriano P , Varmus HE 
Published: October 2019

Abstract
Expression of the Src-family kinases--Src, Hck, and Fgr--increases dramatically during myeloid cell development. Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck-/- or fgr-/- mice have few and subtle myeloid cell deficiencies. To determine whether these limited phenotypes are due to the coexpression of multiple Src-family kinases with overlapping functions, we have intercrossed src-/- mice to hck-/- and fgr-/- mutants to produce double mutants. Two thirds of hck-/- src-/- double mutants die at birth; surviving animals develop a severe form of osteopetrosis, resulting in extreme levels of splenic extramedullary hematopoiesis, anemia, and leukopenia. These hematopoietic defects are caused by abnormalities in the bone marrow environment because hck-/- src-/- mutant stem cells reconstitute a normal hematopoietic system in irradiated wild-type mice. In contrast, fgr-/- src-/- double mutants have no defects beyond those observed in src-/- animals. Cultured normal murine osteoclasts express abundant amounts of Src, Hck, and Fgr and Hck levels are increased in src-/- osteoclasts. These observations suggest that Hck and Src serve partially overlapping functions in osteoclasts and that the expression of Hck in src-/- osteoclasts ameliorates their functional defects.
Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies [published erratum appears in Blood 1996 Oct 1;88(7):2818]
Authors: Kersten MJ , Evers LM , Dellemijn PL , van den Berg H , Portegies P , Hintzen RQ , van Lier RA , von dem Borne AE , van Oers RH 
Published: October 2019

Abstract
Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.
Chemoattractant-induced changes in surface expression and redistribution of a functional ligand for P-selectin on neutrophils
Authors: Dore M , Burns AR , Hughes BJ , Entman ML , Smith CW 
Published: October 2019

Abstract
Adhesion between platelets and neutrophils is mediated through the interaction of P-selectin on activated platelets with a carbohydrate- containing structure on neutrophils, and occurs under both static and shear conditions. Recent studies using flow chambers have shown that neutrophils become activated after binding to surface-adherent platelets expressing P-selectin. The objective of the present study was to investigate the effect of such activation on the interactions of platelet P-selectin with its ligand on neutrophils. Flow cytometric analyses using P-selectin chimeras revealed that activation induced a rapid and marked reduction in chimera binding, with levels of binding decreased by 71% after 15 minutes of stimulation with the chemotactic agent, FMLP. Using a visual assay of platelet-neutrophil rosetting, we showed that the P-selectin ligand was translocated and clustered at the uropod of neutrophils following the shape changes and polarization induced by chemotactic stimulation. Activated neutrophils bound to surface-adherent platelets also displayed the clustering of P-selectin ligand at the uropod, and these neutrophils detached from the platelets when a shear stress (2 dynes/cm2) was applied through the adhesion chamber. These results indicate that chemotactic stimulation of neutrophils induces changes in the surface expression and distribution of a biologically relevant ligand for P-selectin, and that these changes might influence the adhesive interactions occurring between neutrophils and activated platelets.
Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency
Authors: Hirono A , Iyori H , Sekine I , Ueyama J , Chiba H , Kanno H , Fujii H , Miwa S 
Published: October 2019

Abstract
Three unrelated Japanese patients with chronic nonspherocytic hemolytic anemia wer found to have marked deficiency of red blood cell (RBC) reduced glutathoine (GSH) (4.4%, 13.1%, and 6.9% of normal, respectively). A panel of RBC enzyme assays showed that one patient had decreased glutathione synthetase activity and the other two were moderately deficient in gamma-glutamylcystine synthetase. Some family members of each patient showed mild deficiency of the respective enzymes. RBCs of these patients also showed a decreased level of glutathione-S-transferase as in previously described GSH-deficient cases. Hemolytic anemia was their only manifestation, and neither 5- oxoprolinemia nor 5-oxoprolinuria, which are usually associated with to generalized type of glutathione synthetase deficiency, was noted in our patients.
Cross-linking CD7 on myeloblasts results in granulocyte-macrophage colony-stimulating factor production
Authors: Hou Z , Leta E , Jung LK 
Published: October 2019

Abstract
CD7+CD34+ lymphohematopoietic progenitor cells in bone marrow are capable of differentiating into either lymphocytes or myeloid cells. The mechanism whereby these bipotent progenitor cells are regulated is not yet clear. In this study, we investigated the role CD7 may play in the development of bipotent cells using two myeloid progenitor cell lines, KG-1 and KG-1a, as models for such cells. Our data showed that cross-linking CD7 on KG-1 and KG-1a cells induced transcription, translation, and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). Anti-CD7 antibody also augmented the colony formation by KG-1 cells. Protein synthesis in KG-1 cells also increased as a result of anti-CD7 stimulation. These phenomena could be blocked by anti-GM-CSF, and supported the notion that the secreted GM-CSF was the primary mediator of CD7 effects. Together, these findings suggest that the interaction between CD7 and its putative ligand may play an important role in hematopoietic development.
Kaposi's sarcoma (KS)-associated herpesvirus-like DNA sequences in peripheral blood mononuclear cells: association with KS and persistence in patients receiving anti-herpesvirus drugs
Authors: Humphrey RW , O'Brien TR , Newcomb FM , Nishihara H , Wyvill KM , Ramos GA , Saville MW , Goedert JJ , Straus SE , Yarchoan R 
Published: October 2019

Abstract
Herpesvirus-like DNA sequences (KSHV/HHV-8) have recently been described in AIDS-associated Kaposi's sarcoma (KS) lesions. Many questions remain regarding the role of this virus in KS and the therapeutic implications of this finding. In the current study, KSHV/HHV-8 DNA was detected in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus (HIV)-infected patients with KS (34/98) more often than in HIV-infected individuals without KS (12/64, P = .03). The detection of KSHV/HHV-8 DNA did not correlate with the CD4 lymphocyte count. Five patients demonstrated KSHV/HHV-8 DNA in their PBMCs during administration of intravenous foscarnet and/or ganciclovir. The continued detection of KSHV/HHV-8 DNA in the PBMCs of patients receiving these anti-herpesvirus drugs has potential implications regarding the virus-cell relationship of KSHV/HHV-8, as well as for the value of these drugs in treating or preventing KS, but additional studies are needed.