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  • American Society of Hematology  (27)
  • 1
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    MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress
    American Society of Hematology ; 2022
    In:  Blood Vol. 139, No. 8 ( 2022-02-24), p. 1184-1197
    Details
    In: Blood, American Society of Hematology, Vol. 139, No. 8 ( 2022-02-24), p. 1184-1197
    Abstract: Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired antimetabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is reprogramming gene expression in a metabolism-dependent manner. MondoA (also known as Myc-associated factor X–like protein X-interacting protein [MLXIP]), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets, we found that MondoA overexpression is associated with worse survival in pediatric common acute lymphoblastic leukemia (ALL; B-precursor ALL [B-ALL] ). Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and RNA-interference approaches, we observed that MondoA depletion reduces the transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced pyruvate dehydrogenase activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020007932
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Deficient Ribosomal Protein S19 in Diamond-Blackfan Anemia Causes a Reduction in bcl-2 and Bad and Leads to Apoptosis in Erythroid Progenitor Cells.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 131-131
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 131-131
    Abstract: Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein (RP) S19 gene. It is not known how the RPS19 deficiency impairs erythopoiesis and proliferation of hematopoietic progenitors. We have established an in vitro models for RPS19 deficient DBA using lentiviral vector mediated doxycycline (Dox) inducible small interfering RNA (siRNA) against RPS19 (Mol Ther.11:627–637. 2005). Suppression of cell growth and erythroid colony formation correlated with the suppression level of RPS 19, indicating that these cell lines are useful to determine the mechanisms of RPS19 deficient DBA. To elucidate molecular mechanisms in RPS19 deficient DBA, we analyzed cell cycle of Dox induced RPS19 deficient TF-1 cells. RPS19 deficient TF-1 cells showed G0/G1 arrest (82% vs 58%, p & lt;0.05) together with accumlation of p21 and p27, and apoptotic cells detected by Annexin-V analysis also increased compared to control Dox induced TF-1 cells (13% vs 3.1%, p & lt;0.05). Increase of apoptotic cells in RPS19 deficient cells was confirmed by TUNEL assay. Western blot analysis of apoptotic related protein showed that the level of bcl-2 and Bad was decreased in RPS19 deficient TF1 cells compared to control cells. This down-regulation of apoptotic related protein was improved by transduction with lentiviral vector expressing modified RPS19, which is not affected by siRNA but produce normal functional RPS19 protein and rescues the DBA phenotype. Moreover, primary CD34 positive cells from DBA patients detected by Annexin-V analysis also generate a high number of apoptotic cells compared to normal CD34 positive cells during in vitro culture (38% vs 8.9%, n=5, p & lt;0.001). These findings indicate that erythroid progenitor cells are more sensitive to apoptosis than other hematopoietic progenitors and that RPS19 deficiency causes apotosis and accelerated loss of erythroid progenitors in RPS19 deficient DBA.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.131.131
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Cooperative Activity of BRAF F595L and Mutant HRAS in Histiocytic Sarcoma Provides New Insights into Oncogenic BRAF Signaling
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1631-1631
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1631-1631
    Abstract: Activating BRAF mutations, in particular V600E/K, drive many cancers, including a substantial proportion of systemic histiocytic disorders, and mutant BRAF-selective inhibitors are promising therapeutics for these diseases. Activating BRAF alleles are considered mutually exclusive with mutations in RAS family members, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif can coexist with oncogenic RAS and cooperate via transactivation of wildtype RAF proteins and paradoxical MEK/ERK activation. Due to the increasing use of global approaches to tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We used several in vitro experimental systems, including Braf-deficient murine embryonic fibroblasts expressing a regulatable HRAS oncogene, to determine the biochemical properties and cellular effects of a largely uncharacterized mutation, F595L, in the DFG motif of the BRAF activation segment that was identified by clinical exome sequencing in a patient with histiocytic sarcoma and multiorgan involvement and also occurs as somatic alteration in colorectal adenoma or carcinoma, non-small cell lung cancer, cholangiocarcinoma, urothelial cancer, melanoma, and neuroblastoma and as germline mutation in cardio-facio-cutaneous syndrome. In addition, we investigated the interaction between BRAF F595L and a concomitant HRAS Q61R allele, which was present in the same tumor cell clone and occurs as acquired alteration in multiple tumor types and as inherited variant in Costello syndrome. Unlike previously described DFG motif mutants, BRAF F595L is a gain-of-function variant with intermediate activity towards MEK that, in sharp contrast to BRAF V600E, requires an intact dimer interface for downstream signaling. Furthermore, BRAF F595L does not act paradoxically, but nevertheless cooperates with mutant HRAS to induce maximal activity of the MEK-ERK signaling pathway. Of immediate clinical relevance, BRAF F595L shows divergent responses to the mutant BRAF-selective inhibitors vemurafenib and dabrafenib, whereas signaling driven by BRAF F595L with and without mutant HRAS is efficiently blocked by the pan-RAF inhibitors sorafenib and AZ628 and the MEK inhibitor trametinib. Consistent with this, sorafenib treatment led to abrogation of aberrant MEK/ERK signaling in the index case with histiocytic sarcoma driven by BRAF F595L and HRAS Q61R. Mutation data from patients and cell lines, representing 18 different tumor entities, show that BRAF F595L as well as other BRAF mutants with intermediate signaling activity coincide with mutant RAS in at least 40% and 23% of cases, respectively. These data define a distinct class of activating BRAF mutations that cooperate with oncogenic RAS in a non-paradoxical fashion, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway, and underscore the value of comprehensive genomic profiling for uncovering the vulnerabilities of individual tumors. Disclosures Off Label Use: Administration of sorafenib in a patient with histiocytic sarcoma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1631.1631
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Hematopoietc Stem Cell Targeted Neonatal Gene Therapy Cures oc/oc Mice from Osteopetrosis.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 456-456
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 456-456
    Abstract: Infantile malignant osteopeterosis (IMO) is a progressive, rare autosomal recessive disorder affecting osteoclast function. 50% of the affected children have a mutation in the Tcirg1 gene coding for one subunit of an osteoclast specific proton pump, OC116. The non-resorbed dense, sclerotic bones cause symptoms including pancytopenia and progressive visual loss and ultimately death. So far, the only curative treatment is hematopoietic stem cell (HSC) transplantation. The oc/oc mouse has a mutation in the gene homologous to Tcirg1 giving rise to similar symptoms as in patients leading to death of the mice at the age of 3–4 weeks. We have previously shown that the oc/oc mouse can be successfully treated with neonatal transplantation of normal HSC leading to prolonged survival and reversal of osteopetrosis (M. Johansson et al., Exp. Hematology34;242, 2006). In the current study we set out to develop HSC directed gene therapy for osteopetrosis in the oc/oc mouse model. As the bone marrow compartment is severely reduced in the oc/oc mouse fetal liver (FL) cells depleted of Ter119+ erythroid cells were used as a source of hematopoietic stem cells. We first established that wild type Ter119 depleted FL cells marked with a GFP vector and transplanted to newborn oc/oc mice i.p. could correct the osteopetrotic phenotype just as was shown for fresh bone marrow cells previously. Subsequently, Ter119 depleted FL cells from oc/oc mice were transduced with a retroviral vector expressing OC116 and GFP. In vitro transduction efficiency was 60–85%. One-day-old oc/oc mice were irradiated (400cGy) and transplanted i.p. with the transduced FL cells (1–3.5x106). 7 out of 14 mice survived past the expected lifespan and had 8–53% GFP+ cells in the peripheral blood at 3, 6 and 12 weeks. Analysis of bone structure with X-ray and histopathology showed an improvement at 8 weeks and an almost normal structure at 18 weeks, indicating induction of osteoclast activity. In vitro culture of osteoclasts from bone marrow from transplanted animals on bovine bone slices showed GFP marked osteoclasts and bone resorption, albeit at lower levels than for wild type cells. In the oc/oc mouse there is a block in B-lymphopoiesis leading to a reduced number of B-lymphocytes in the peripheral blood. In treated mice a reversal of this deficiency was observed. In summary we have demonstrated that the osteoclast defect seen in oc/oc mice can be successfully corrected by neonatal transplantation of gene modified hematopoietic stem cells and that this can lead to long-term survival of treated mice. This represents a significant step towards the development of gene therapy for osteopetrosis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.456.456
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 5
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    Recurrent Germline Variant in the Cohesin Complex Gene RAD21 Predisposes Children to Lymphoblastic Leukemia and Lymphoma
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Abstract: Introduction: Cohesin complex genes are commonly mutated in cancer particularly in myeloid malignancies. Yet patients with germline mutations in cohesin genes, leading to cohesinopathies like Cornelia-de-Lange syndrome (CdLS) are generally not known to be tumor-prone. The complex plays a major role in chromosome alignment and segregation (Uhlmann, Nature Reviews Molecular Cell Biology, 2016), homologous recombination-driven DNA repair (Ström et al., Molecular Cell, 2004) and regulation of gene expression (Busslinger et al., Nature, 2017). To deepen the understanding of cohesin variants in cancer predisposition, we performed TRIO Sequencing in two independent pediatric cancer cohorts. Thereby, we identified a novel recurrent heterozygous germline variant in the cohesin gene RAD21 not described in CdLS patients , located in the binding domain of the cofactors WAPL and PDS5B . Methods: Whole exome sequencing (WES) in a TRIO (child-parent datasets) setting was carried out in two independent, unselected cancer cohorts (TRIO-D, n=158 (Wagener et al., European Journal of Human Genetics, 2021) and TRIO-DD, n=60). To investigate the oncogenic potential of the novel RAD21 variant molecular and functional assessment was performed focusing on potential implications on the complex. Results: The newly identified RAD21 variant at amino acid position 298 resulting in a Proline to Serine (p.P298S) and a Proline to Alanine exchange, respectively, (p.P298A) is only rarely mutated in the general population (gnomAD database n=118,479; RAD21 p.P298S MAF & lt;10 -6 and RAD21 p.P298A MAF & lt;10 -5). While both patients did not show any signs of CdLS, they both have a remarkable family history of cancer. Patient 1 (13y) was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) whose father had died from breast cancer (41y), while patient 2 (2y) presented with precursor B-cell lymphoblastic lymphoma (pB-LBL) whose uncle had died from pediatric cancer of unknown subtype (8y). To assess the influence of RAD21 p.P298S/A on the binding capacity of the complex, RAD21 variants and the wildtype (WT) were cloned and transfected into HEK293T cells, respectively. Immunoprecipitation analysis of RAD21 with the cofactors WAPL and PDS5B showed no differential binding between the WT and the variants, suggesting that RAD21 p.P298S/A does not impact the formation of the complex. Nevertheless, on a transcriptional level 83 genes were significantly differentially expressed in RAD21 p.P298S and p.P298A compared to the wildtype (fc & gt;1.5, adj. p-value & lt;0.05) with enrichment of genes in p53 signaling pathways. We further observed an increased number of γH2AX and 53BP1 co-localized foci compared to the WT (p≤0.01; Student's t-test). In line, following ionizing radiation, primary patients' samples showed increased cell cycle arrest at G2/M cell-cycle stage compared to a healthy control (p.P298S: p=0.0049 [6Gy]; p=0.0026 [10Gy] ; p.P298A: p=0.0054 [6Gy]; p=0.0006 [10Gy] ; Student's t-test). For cross-validation of the germline variant RAD21 p.P298S/A and its potential role in pediatric lymphoblastic malignancies, we analysed a third cohort of 150 children with relapsed ALL (IntReALL) for RAD21 p.P298S/A. We again identified RAD21 p.P298A in a boy (12y) with B-cell precursor acute lymphoblastic leukemia. To compare our data to a non-pediatric cancer setting, a cohort of 2300 young adults ( & lt;51 years) with cancer was mined (MASTER program). Here, one patient carrying RAD21 p.P298A with a solid tumor was identified. Therefore, amongst all cohorts, RAD21 p.P298S/A was found to be enriched in pediatric vs. adult cancers (3/479 vs. 1/2299; Fisher's exact test; p=0.018). Conclusion: Taken together, we present for the first time the potential role of RAD21 germline variants in pediatric lymphoblastic malignancies. This may shed new light on the many roles of the cohesin complex and its implication outside the typical syndromal presentation. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-150284
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Molecular Characteristics of Diffuse Large B-Cell Lymphoma and Correlation with Baseline Metabolic Tumor Volume (MTV), Interim Positron Emission Tomography (iPET) and Outcome in the PETAL Trial
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4188-4188
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4188-4188
    Abstract: Introduction: Treatment results in diffuse large B-cell lymphoma (DLBCL) are heterogeneous. Established risk models like the International Prognostic Index (IPI) and molecular lymphoma features such as MYC translocations and the cell of origin (COO) subtype are prognostic of outcome. A positive iPET scan after 2 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has recently been shown to predict poor outcome independent of the IPI (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial [PETAL]; Dührsen et al., J Clin Oncol 36:2024, 2018). Another PET-derived parameter of potential prognostic significance is baseline MTV. This retrospective analysis of lymphoma biopsies from the PETAL trial investigated the relationship between molecular lymphoma features and PET parameters. Methods: Available lymphoma specimens were analyzed for COO by immunohistochemistry employing the Hans-classifier (HC) and by gene expression (GE) using the HTG EdgeSeq System (HTG Molecular Diagnostics). MYC and BCL2 and/or BCL6 translocations ("double-hit" [DH]) were assessed by fluorescence in situ hybridization (FISH). MTV was determined applying the 41% SUVmax segmentation method, and iPET was evaluated using the deltaSUVmax method. Association between iPET result and molecular lymphoma features was assessed by risk ratios (RR). Survival curves of time-to-event endpoints were compared using hazard ratios (HR) from Cox regression and the log-rank test. Results: Of 609 DLBCL patients treated in the PETAL trial, 63 had a positive iPET. 134 of 267 DLBCL biopsies available for HC analysis (50.2%) were classified as non-germinal center B-cell (non-GCB) and 133 (49.8%) as GCB. COO analysis by GE revealed an activated B-cell (ABC) type in 122 (51.1%) and a GCB type in 102 (42.7%) of 239 available biopsies (n=7 [2.9%] unclassified, n=8 [3.3%] failed quality control). Concordance between HC and GE was found in 165 of 197 biopsies studied by both methods (83.8%). MYC breaks were found in 27 (10.7%) and MYC amplifications in 48 (19.0%) of 253 cases studied by FISH. A DH lymphoma was diagnosed in 16 of 253 cases (6.3%). Complete information on HC, GE and DH status was available for 170 cases. The relationship is depicted in figure 1. COO classification by either HC or GE was not correlated with baseline MTV, iPET result, event-free (EFS) survival or overall (OS) survival. By contrast, DH status was correlated with positive iPET (RR 2.30 [95% CI, 0.76 to 6.96]) and inferior outcome as shown in figure 2 (EFS: HR 2.04 [95% CI, 1.02 to 4.07] ; p=.044; OS: HR 3.00 [95% CI, 1.34 to 6.71]; p=.007). There was no co rrelation between DH status and MTV. iPET-positive DLBCL harbored MYC breaks more frequently than iPET-negative DLBCL (RR 3.29 [95% CI, 1.40 to 7.77]). A similar trend was observed in 72 cases tested for BCL2 breaks (RR 1.30 [95% CI, 0.44 to 3.84] ) and 74 cases tested for BCL6 breaks (RR 1.85 [95% CI, 0.59 to 5.80]). Conclusion: HC and GE showed good concordance with respect to COO classification, but COO was not correlated with MTV, iPET, EFS or OS. By contrast, MYC-rearranged lymphomas with or without BCL2 or BCL6 breaks were statistically significantly associated with a positive iPET, and DH lymphomas were correlated with poor outcome. Yet, the unfavorable prognosis of iPET-positive DLBCL cannot solely be explained by MYC translocations because most iPET-positive lymphomas lacked this genetic anomaly. Our results strengthen the role of iPET as a prognostic tool, independent not only of IPI, but also of COO status and MYC translocation. Disclosures Richter: HTG Molecular Diagnostics, Inc.: Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Gärtner:HTG Molecular Diagnostics, Inc.: Employment. Duehrsen:Amgen: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Amgen: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-112815
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 7
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    Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia
    American Society of Hematology ; 2018
    In:  Blood Advances Vol. 2, No. 13 ( 2018-07-10), p. 1572-1579
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    In: Blood Advances, American Society of Hematology, Vol. 2, No. 13 ( 2018-07-10), p. 1572-1579
    Abstract: TL in LSCs is significantly shortened at diagnosis of CML and correlates with LSC burden. TL in nonleukemic myeloid cells in deep molecular remission is unaffected by long-term TKI treatment.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2018017772
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 8
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    Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency
    American Society of Hematology ; 2008
    In:  Blood Vol. 111, No. 3 ( 2008-02-01), p. 1512-1514
    Details
    In: Blood, American Society of Hematology, Vol. 111, No. 3 ( 2008-02-01), p. 1512-1514
    Abstract: Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of factor H–related proteins CFHR1 and CFHR3 as predisposing factor for aHUS. Here we identify in an extended cohort of 147 aHUS patients that 16 juvenile individuals (ie, 11%) who either lacked the CFHR1/CFHR3 completely (n = 14) or showed extremely low CFHR1/CFHR3 plasma levels (n = 2) are positive for factor H (CFH) autoantibodies. The binding epitopes of all 16 analyzed autoantibodies were localized to the C-terminal recognition region of factor H, which represents a hot spot for aHUS mutations. Thus we define a novel subgroup of aHUS, termed DEAP HUS (deficiency of CFHR proteins and CFH autoantibody positive) that is characterized by a combination of genetic and acquired factors. Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2007-09-109876
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 9
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    Recurrent CDKN1B (p27) mutations in hairy cell leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 8 ( 2015-08-20), p. 1005-1008
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    In: Blood, American Society of Hematology, Vol. 126, No. 8 ( 2015-08-20), p. 1005-1008
    Abstract: Somatic CDKN1B (p27) mutations were identified in 16% (13/81) of HCL patients and coexist with BRAFV600E mutations. CDKN1B is the second most common mutated gene in HCL implicating altered cell cycle regulation and/or senescence in HCL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2015-04-643361
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 10
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    Apoptotic Change Is a Major Reason for Defect in Early Erythroid Development in Cell Line Models for Ribosomal Protein (RP) S19 Deficient Diamond-Blackfan Anemia.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2840-2840
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2840-2840
    Abstract: Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein (RP) S19 gene. It is not known how the RPS19 deficiency impairs erythopoiesis and proliferation of hematopoietic progenitors. The majority of cases appear to result from an intrinsic disorder of the erythroid progenitor that involves its inability to respond normally to inducers of erythroid proliferation and differentiation. Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. However, so far, no receptor-ligand defects have yet been identified. We have established an in vitro models for RPS19 deficient DBA using lentiviral vector mediated doxycycline (Dox) inducible small interfering RNA (siRNA) against RPS19 (Blood102:504a, 2003). To analyze the effect of suppression of RPS19 for erythroid differentiation, we used cytokine dependent TF-1 cell lines (CD34+, CD71+, GFAlow) together with new established cytokine independent K562 cell lines (CD34−, CD71+, GFAhigh). We established two types of cell lines (TF-1A, K562A and TF1B, K562B) using different siRNA against RPS19. Five days after Dox induction, RPS19 protein level was suppressed to 45–55% in TF-1A and K562A, 65–75% in TF1B and K562B compared to control scramble transduced cell lines (TF1S, K562S) by western blot analysis. Suppression of cell growth and colony formation correlated with the suppression level of RPS 19 in TF1A, B and K562A, B cells. In contrast, after stimulation with Epo, glycophorin A expression, measured by flow cytometry, and hemoglobin content (DAF staining) showed suppression of erythroid differentiation only in TF1A and TF1B but not in K562A and K562B. Since Epo induces the stimulation of Jak2 tyrosine kinase which leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated such as Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. Therefore, we analyzed Epo stimulated signal transduction in these cell lines. However, no abnormal signal transduction could be detected in any of the cell lines. Cell cycle analysis showed that the percentage of cells in the G0/G1 phase increased and apoptotic cells detected by Annexin-V analysis also increased in TF1 (A & lt;B) and K562 (A & lt;B) cells. Western blot analyzed p21 showed that the level of p21 was increased in TF1 (A & lt;B) and K562 (A & lt;B) cells. These results indicate that Epo triggered onset of terminal maturation is intact in RPS19 deficient DBA cell line models. We speculate that apoptotic change by suppressed RPS19 may be one of the major reason for the accelerated loss of erythroid progenitor clonogenicity in RPS19 deficient DBA. These cell lines are useful to determine the mechanisms of RPS19 deficient DBA.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.2840.2840
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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