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The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy (2013)

Stepensky, P., Saada, A., Cowan, M., Tabib, A., Fischer, U., Berkun, Y., Saleh, H., Simanovsky, N., Kogot-Levin, A., Weintraub, M., Ganaiem, H., Shaag, A., Zenvirt, S., Borkhardt, A., Elpeleg, O., Bryant, N. J., Mevorach, D.

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2013-06-21

Description: Severe congenital neutropenia as well as primary myelofibrosis are rare in infancy. Elucidation of the underlying mechanism is important because it extends our understanding of the more common adult forms of these disorders. Using homozygosity mapping followed by exome sequencing, we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia, which was refractory to granulocyte CSF, from defective platelet aggregation and myelofibrosis. The mutation segregated in the families, was not present in controls, affected a highly conserved codon, and apparently destabilized the Vps45 protein, which was reduced in the patients’ leukocytes. Introduction of the corresponding mutation into yeast resulted in reduced cellular levels of Vps45 and also of the cognate syntaxin Tlg2, which is required for membrane traffic through the endosomal system. A defect in the endosomal-lysosomal pathway, the homologous system in humans, was suggested by the absence of lysosomes in the patients’ fibroblasts and by the depletion of α granules in their platelets. Importantly, accelerated apoptosis was observed in the patients’ neutrophils and bone marrow. This is the first report of a Vps45-related disease in humans, manifesting by neutropenia, thrombasthenia, myelofibrosis, and progressive bone marrow failure.

Keywords: Pediatric Hematology, Phagocytes, Granulocytes, and Myelopoiesis

Print ISSN: 0006-4971

Electronic ISSN: 1528-0020

Topics: Biology , Medicine

Published by American Society of Hematology (ASH)

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Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation (2015)

Fioredda, F., Iacobelli, S., van Biezen, A., Gaspar, B., Ancliff, P., Donadieu, J., Aljurf, M., Peters, C., Calvillo, M., Matthes-Martin, S., Morreale, G., van 't Veer-Tazelaar, N., de Wreede, L., Al Seraihy, A., Yesilipek, A., Fischer, A., Bierings, M., Ozturk, G., Smith, O., Veys, P., Ljungman, P., Peffault de Latour, R., Sanchez de Toledo Codina, J., Or, R., Ganser, A., Afanasyev, B., Wynn, R., Kalwak, K., Marsh, J., Dufour, C., on behalf of the Severe Aplastic Anemia the Inborn Error, and the Pediatric Disease Working Parties of the European Society for Blood and Bone Marrow Transplantation (EBMT) and Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE)

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2015-10-16

Description: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce. We report on the outcome of 136 SCN patients who underwent HSCT between 1990 and 2012 in European and Middle East centers. The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%. In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS. Frequency of graft failure was 10%. Cumulative incidence (day +90) of acute graft-versus-host disease (GVHD) grade 2-4 was 21%. In multivariate analysis, HLA-matched related donor and prophylaxis with cyclosporine A and methotrexate were associated with lower occurrence of acute GVHD. Cumulative incidence (1 year) of chronic GVHD was 20%. No secondary malignancies occurred after a median follow-up of 4.6 years. These data show that the outcome of HSCT for SCN from HLA-matched donors, performed in recent years, in patients younger than 10 years is acceptable. Nevertheless, given the TRM, a careful selection of HSCT candidates should be undertaken.

Keywords: Hematopoiesis and Stem Cells, Pediatric Hematology, Transplantation, Free Research Articles, Phagocytes, Granulocytes, and Myelopoiesis, CME article, Clinical Trials and Observations

Print ISSN: 0006-4971

Electronic ISSN: 1528-0020

Topics: Biology , Medicine

Published by American Society of Hematology (ASH)

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Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice (2016)

Maschalidi, S., Sepulveda, F. E., Garrigue, A., Fischer, A., de Saint Basile, G.

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2016-07-08

Description: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, characterized by severe hyperinflammation and immunopathological manifestations in several tissues. These features result from organ infiltration by overactivated CD8 T-cells and macrophages, which produce high levels of pro-inflammatory cytokines, such as IFN-, TNF-α, IL-6, and IL-18. Recently, several Janus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been developed as immunosuppressive agents. They have proven beneficial effects in the treatment of myeloproliferative disorders and inflammatory conditions. To determine whether pharmacological inhibition of the JAK1/2 not only prevents the onset of HLH immunopathology but also is effective against existing HLH, cytotoxicity-impaired Prf1 –/– and Rab27a –/– mice with full-blown HLH syndrome were treated with a clinically relevant dose of ruxolitinib. In vivo, ruxolitinib treatment suppressed signal transducer and activator of transcription 1 activation and led to recovery from HLH manifestations in both murine models. In the Prf1 –/– mice, these beneficial effects were evidenced by a greater survival rate, and in both murine models, they were evidenced by the correction of blood cytopenia and a rapid decrease in serum IL-6 and TNF-α levels. During ruxolitinib treatment, liver tissue damage receded concomitantly with a decrease in the number of infiltrating inflammatory macrophages and an increase in the number of alternatively activated macrophages. In Rab27a –/– mice, central nervous system involvement was significantly reduced by ruxolitinib therapy. Our findings demonstrate that clinically relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful consequences of macrophage overactivation characterizing HLH in 2 murine models. The results could be readily translated into the clinic for the treatment of primary, and perhaps even secondary, forms of HLH.

Keywords: Immunobiology

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Electronic ISSN: 1528-0020

Topics: Biology , Medicine

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Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning (2013)

Boelens, J. J., Aldenhoven, M., Purtill, D., Ruggeri, A., De; For, T., Wynn, R., Wraith, E., Cavazzana-Calvo, M., Rovelli, A., Fischer, A., Tolar, J., Prasad, V. K., Escolar, M., Gluckman, E., O'Meara, A., Orchard, P. J., Veys, P., Eapen, M., Kurtzberg, J., Rocha, V., on behalf of all participating centers from Eurocord, Inborn Errors Working Party of European Blood and Marrow Transplant group, Duke University, and the Centre for International Blood and Marrow Research

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2013-05-10

Description: We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism ( P = .039) and normal enzyme levels ( P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

Keywords: Pediatric Hematology, Transplantation, Free Research Articles

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Electronic ISSN: 1528-0020

Topics: Biology , Medicine

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Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening (2018)

Schäfer, D., Olsen, M., Lähnemann, D., Stanulla, M., Slany, R., Schmiegelow, K., Borkhardt, A., Fischer, U.

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2018-02-16

Keywords: Pediatric Hematology, Lymphoid Neoplasia

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Electronic ISSN: 1528-0020

Topics: Biology , Medicine

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Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL (2012)

Morak, M., Attarbaschi, A., Fischer, S., Nassimbeni, C., Grausenburger, R., Bastelberger, S., Krentz, S., Cario, G., Kasper, D., Schmitt, K., Russell, L. J., Potschger, U., Stanulla, M., Eckert, C., Mann, G., Haas, O. A., Panzer-Grumayer, R.

American Society of Hematology (ASH)

In: Blood

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Publication Date: 2012-12-21

Description: The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology and Oncology Berlin-Frankfurt-Münster (AIEOP-BFM) 2000 protocols. To investigate whether and to what extent different clone sizes influence disease and relapse development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM-ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal translocations and high hyperdiploidy, representing approximately 50% of all cases, 67 (25%) were P2RY8-CRLF2 positive. The respective clone sizes were ≥ 20% in 27% and 〈 20% in 73% of them. The cumulative incidence of relapse of the entire fusion-positive group was clone size independent and significantly higher than that of the fusion-negative group (35% ± 8% vs 13% ± 3%, P = .008) and primarily confined to the non–high-risk group. Of 22 P2RY8-CRLF2 –positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone. We conclude that the majority of P2RY8-CRLF2 –positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2 –positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone.

Keywords: Free Research Articles, Lymphoid Neoplasia, 〈a href="/content/by/section/Editorials"〉Editorials〈/a〉, Clinical Trials and Observations

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Ice-nucleating bacteria control the order and dynamics of interfacial water (2016)

Pandey, R., Usui, K., Livingstone, R. A., Fischer, S. A., Pfaendtner, J., Backus, E. H. G., Nagata, Y., Fröhlich-Nowoisky, J., Schmüser, L., Mauri, S., Scheel, J. F., Knopf, D. A., Pöschl, U., Bonn, M., Weidner, T.

American Association for the Advancement of Science (AAAS)

In: Science Advances

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Publication Date: 2016-04-28

Description: Ice-nucleating organisms play important roles in the environment. With their ability to induce ice formation at temperatures just below the ice melting point, bacteria such as Pseudomonas syringae attack plants through frost damage using specialized ice-nucleating proteins. Besides the impact on agriculture and microbial ecology, airborne P. syringae can affect atmospheric glaciation processes, with consequences for cloud evolution, precipitation, and climate. Biogenic ice nucleation is also relevant for artificial snow production and for biomimetic materials for controlled interfacial freezing. We use interface-specific sum frequency generation (SFG) spectroscopy to show that hydrogen bonding at the water-bacteria contact imposes structural ordering on the adjacent water network. Experimental SFG data and molecular dynamics simulations demonstrate that ice-active sites within P. syringae feature unique hydrophilic-hydrophobic patterns to enhance ice nucleation. The freezing transition is further facilitated by the highly effective removal of latent heat from the nucleation site, as apparent from time-resolved SFG spectroscopy.

Electronic ISSN: 2375-2548

Topics: Natural Sciences in General

Published by American Association for the Advancement of Science (AAAS)

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Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival (2018)

Gast, C. E., Silk, A. D., Zarour, L., Riegler, L., Burkhart, J. G., Gustafson, K. T., Parappilly, M. S., Roh-Johnson, M., Goodman, J. R., Olson, B., Schmidt, M., Swain, J. R., Davies, P. S., Shasthri, V., Iizuka, S., Flynn, P., Watson, S., Korkola, J., Courtneidge, S. A., Fischer, J. M., Jaboin, J., Billingsley, K. G., Lopez, C. D., Burchard, J., Gray, J., Coussens, L. M., Sheppard, B. C., Wong, M. H.

American Association for the Advancement of Science (AAAS)

In: Science Advances

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Publication Date: 2018-09-13

Description: High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated but cannot explain all aspects of tumor heterogeneity. We present evidence that fusion of neoplastic cells with leukocytes (for example, macrophages) contributes to tumor heterogeneity, resulting in cells exhibiting increased metastatic behavior. Fusion hybrids (cells harboring hematopoietic and epithelial properties) are readily detectible in cell culture and tumor-bearing mice. Further, hybrids enumerated in peripheral blood of human cancer patients correlate with disease stage and predict overall survival. This unique population of neoplastic cells provides a novel biomarker for tumor staging, as well as a potential therapeutic target for intervention.

Electronic ISSN: 2375-2548

Topics: Natural Sciences in General

Published by American Association for the Advancement of Science (AAAS)

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