Publications by authors named "Ana-Iris Schiefer"

42 Publications

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematological Cancers and Identifies Exceptional Responders.

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

Platform Austria for Chemical Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients' tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0538DOI Listing
October 2021

Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21).

Blood Adv 2021 05;5(10):2481-2489

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).
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http://dx.doi.org/10.1182/bloodadvances.2020003605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152510PMC
May 2021

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

J Clin Immunol 2021 Aug 30;41(6):1272-1290. Epub 2021 Apr 30.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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http://dx.doi.org/10.1007/s10875-021-01031-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086229PMC
August 2021

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Nat Genet 2021 04 29;53(4):500-510. Epub 2021 Mar 29.

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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http://dx.doi.org/10.1038/s41588-021-00803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161PMC
April 2021

Heat shock protein 90α in thymic epithelial tumors and non-thymomatous myasthenia gravis.

Oncoimmunology 2020 05 13;9(1):1756130. Epub 2020 May 13.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Thymic epithelial tumors (TETs) are rare malignancies with unique association to the autoimmune disease myasthenia gravis (MG). Heat shock proteins (HSPs) harbor great potential as cancer biomarkers and HSP inhibitors approach clinical cancer therapy.

Methods: To explore HSP pathophysiology, we assessed sera (immunoassays) and tissues (immunohistochemistry) of TETs (and thymic tissues) for HSP27, phosphorylated (p)HSP27, HSP70 and HSP90α expression in 114 TETs and 26 non-thymomatous MG patients undergoing extended thymectomy.

Results: Serum concentrations of HSP90α were significantly increased in patients with thymic carcinomas, thymomas, thymic neuroendocrine tumors and non-thymomatous MG compared to patients who underwent thymectomy revealing regular thymic morphology or controls. In thymoma patients, high serum HSP90α represented a significantly worse prognostic factor for free-from-recurrence, and complete tumor resection led to decreased levels. The expression of HSP90 in nuclei and cytoplasm of tumor cells and non-neoplastic lymphocytes varied with WHO histological subtype. HSP90 was expressed in centroblasts of thymic germinal centers in MG patients. Higher pHSP27 serum concentrations were observed in seropositive MG and those not treated with steroids.

Conclusions: HSP data suggest high potential for HSPs as TET cancer biomarkers or as candidates for targeted therapy. Caution is warranted in TET patients with associated MG overexpressing HSPs.
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http://dx.doi.org/10.1080/2162402X.2020.1756130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458630PMC
May 2020

Myelomonocytic Skewing In Vitro Discriminates Subgroups of Patients with Myelofibrosis with A Different Phenotype, A Different Mutational Profile and Different Prognosis.

Cancers (Basel) 2020 Aug 14;12(8). Epub 2020 Aug 14.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E. Myelomonocytic skewing as indicated by a CFU-GM/BFU-E ratio ≥ 1 was found in 26/81 (32%) MF patients as compared to 1/98 (1%) in normal individuals. Patients with myelomonocytic skewing as compared to patients without skewing had higher white blood cell and blast cell counts, more frequent leukoerythroblastic features, but lower hemoglobin levels and platelet counts. The presence of myelomonocytic skewing was associated with a higher frequency of additional mutations, particularly in genes of the epigenetic and/or splicing machinery, and a significantly shorter survival (46 vs. 138 mo, < 0.001). The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with MF with a different phenotype, a different mutational profile and a different prognosis. Our findings may be important for the understanding and management of MF.
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http://dx.doi.org/10.3390/cancers12082291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464756PMC
August 2020

PD-L1 and HER2 Expression in Gastroesophageal Cancer: a Matched Case Control Study.

Pathol Oncol Res 2020 Oct 5;26(4):2225-2235. Epub 2020 May 5.

Comprehensive Cancer Center Vienna, Upper GI Tumors Unit, Medical University of Vienna, Wien, Austria.

Immunotherapy with check-point inhibitors serves as a promising treatment strategy in patients with upper gastrointestinal (GI) tumors. Human epidermal growth factor receptor 2 (HER2) is the only identified therapeutic target in upper GI tumors, whose potential interaction with programmed death-ligand 1 (PD-L1) is unknown. The aim of this study was the investigation of PD-L1 and HER2 in upper GI tumors. We retrospectively identified patients with HER2 positive gastroesophageal cancers and matched them with a HER2 negative group. We investigated the tumor specimens for HER2 status and PD-L1 expression, with the following assessments being performed: i) staining of tumor cells in terms of tumor proportion score (TPS), ii) staining for tumor-associated immune cells (TAIs), iii) interface pattern and iv) combined positive score (CPS). Both HER2 positive and negative group consisted of 59 patients. Expression of PD-L1 in TAIs and interface pattern were associated with a favorable outcome (p = 0.02, HR = 0.8; p = 0.04, HR = 0.39; respectively) in patients with localized disease, whereas TPS was associated with an unfavorable outcome in patients with advanced tumor (p = 0.02, HR = 1.4). These effects were HER2 independent. PD-L1 expression in its different assessment is equally observed in HER2 positive and negative patients. Future studies will show whether dual inhibition of HER2 and PD-L1 improves survival of this selected patient population.
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http://dx.doi.org/10.1007/s12253-020-00814-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471145PMC
October 2020

Clinical prognostic scores for patients with thymic epithelial tumors.

Sci Rep 2019 12 9;9(1):18581. Epub 2019 Dec 9.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Several inflammation-based prognostic scores emerged in various types of cancer to predict clinical outcomes. So far, no accurate pre-treatment scoring systems exist for patients with thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs). Therefore, we sought to test the prognostic value of different clinical composite scores and their components, identify optimal cut-off values for TETs as well as combine predictive components to new suitable prognostic scores. One hundred eighty-four patients with TETs undergoing surgical tumor resection were analyzed. A significant advantage in Freedom-from-Recurrence and/or Cause-specific survival (CSS) was evident for patients with high Advanced-Lung- Cancer-Inflammation-Index, low CRP-Fibrinogen-Score (CFS), low Glasgow-Prognostic-Score (GPS), low high-sensitivity-modified GPS, low TET-adapted GPS (TET-aGPS) and low Systemic-Immune-Inflammation Index. On multivariable analysis high TET-aGPS (HR = 14.9;p = 0.001), incomplete resection status (HR = 13.5;p = 0.001) and TC (HR = 26.0;p = 0.001) were significant independent prognostic factors for worse CSS. The CFS had the highest coefficient of determination (R = 0.188) to predict tumor recurrence of all composite scores, comprising CRP (R = 0.141) and fibrinogen (R = 0.158), the best single factor predictors. Inflammation-based prognostic scores and selected components are suitable to predict survival and/or tumor recurrence in TET patients undergoing primary surgery. Due to excellent long-term survival and frequent tumor recurrence, cut-off values were tailored to increase prognostic power.
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http://dx.doi.org/10.1038/s41598-019-54906-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901461PMC
December 2019

Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors.

Sci Rep 2019 11 22;9(1):17359. Epub 2019 Nov 22.

Christian Doppler Laboratory for Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna, Vienna, Austria.

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFβ family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.
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http://dx.doi.org/10.1038/s41598-019-53671-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874542PMC
November 2019

PD-L1 and PD1 expression in post-transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter- and intra-individual descriptive study covering the whole spectrum of PTLD categories.

Cancer Med 2019 08 3;8(10):4656-4668. Epub 2019 Jul 3.

Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.

Therapy of children with post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD-L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD-L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD-L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra-individual assessment of PD-L1/PD1 expression. We observed lower PD-L1 and higher PD1 expression in non-destructive lesions, and higher PD-L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B-cell lymphomas (DLBCL, n = 10/21). The amount of PD-L1- and PD1-positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD-L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non-destructive early lesions. PD-L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune- and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD-L1 and PD1 in all PTLD categories.
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http://dx.doi.org/10.1002/cam4.2394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712474PMC
August 2019

Transformed mucosa-associated lymphoid tissue lymphomas: A single institution retrospective study including polymerase chain reaction-based clonality analysis.

Br J Haematol 2019 08 24;186(3):448-459. Epub 2019 May 24.

Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.

Given the lack of consistent data regarding the clinico-pathological features and clonal lymphomagenesis of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra-gastric; median follow-up 52 months) diagnosed with HT at the Medical University Vienna 1999-2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)-based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6-202 months) after diagnosis of MALT lymphoma. By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82-202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5-33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.
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http://dx.doi.org/10.1111/bjh.15953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771836PMC
August 2019

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia.

Haematologica 2020 31;105(2):435-447. Epub 2020 Jan 31.

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Recurrent gain-of-function mutations in the transcription factors and much more in were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive or variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8 T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8 T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.
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http://dx.doi.org/10.3324/haematol.2019.216986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012494PMC
April 2021

Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells.

Blood 2019 06 8;133(24):2597-2609. Epub 2019 Apr 8.

Research Unit Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Munich, Germany.

CD30 is expressed on a variety of B-cell lymphomas, such as Hodgkin lymphoma, primary effusion lymphoma, and a diffuse large B-cell lymphoma subgroup. In normal tissues, CD30 is expressed on some activated B and T lymphocytes. However, the physiological function of CD30 signaling and its contribution to the generation of CD30 lymphomas are still poorly understood. To gain a better understanding of CD30 signaling in B cells, we studied the expression of CD30 in different murine B-cell populations. We show that B1 cells expressed higher levels of CD30 than B2 cells and that CD30 was upregulated in IRF4 plasmablasts (PBs). Furthermore, we generated and analyzed mice expressing a constitutively active CD30 receptor in B lymphocytes. These mice displayed an increase in B1 cells in the peritoneal cavity (PerC) and secondary lymphoid organs as well as increased numbers of plasma cells (PCs). TI-2 immunization resulted in a further expansion of B1 cells and PCs. We provide evidence that the expanded B1 population in the spleen included a fraction of PBs. CD30 signals seemed to enhance PC differentiation by increasing activation of NF-κB and promoting higher levels of phosphorylated STAT3 and STAT6 and nuclear IRF4. In addition, chronic CD30 signaling led to B-cell lymphomagenesis in aged mice. These lymphomas were localized in the spleen and PerC and had a B1-like/plasmablastic phenotype. We conclude that our mouse model mirrors chronic B-cell activation with increased numbers of CD30 lymphocytes and provides experimental proof that chronic CD30 signaling increases the risk of B-cell lymphomagenesis.
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http://dx.doi.org/10.1182/blood.2018880138DOI Listing
June 2019

downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels.

Blood 2018 11 13;132(22):2389-2400. Epub 2018 Sep 13.

Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely , which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing in tFL by binding in its upstream region. This MYC-mediated repression of in B cells is not dependent on LIN28A/B proteins, which influence the maturation of precursor () in myeloid cells. We also demonstrated that low levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC//FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
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http://dx.doi.org/10.1182/blood-2018-06-855502DOI Listing
November 2018

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

Cancer Med 2018 09 16;7(9):4447-4455. Epub 2018 Aug 16.

Division of Hematology and HCT, City of Hope, Duarte, California.

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.

Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).

Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).

Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
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http://dx.doi.org/10.1002/cam4.1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144246PMC
September 2018

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Blood 2018 08 14;132(7):694-706. Epub 2018 Jun 14.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.
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http://dx.doi.org/10.1182/blood-2017-10-810739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115916PMC
August 2018

Prognostic and diagnostic impact of fibrinogen, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio on thymic epithelial tumors outcome.

Oncotarget 2018 Apr 24;9(31):21861-21875. Epub 2018 Apr 24.

Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.

Background: Peripheral blood-derived inflammation-based markers, such as Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Fibrinogen have been identified as prognostic markers in various solid malignancies. Here we aimed to investigate the prognostic and diagnostic impact of NLR, PLR, and Fibrinogen in patients with thymic epithelial tumors (TETs).

Results: Pretreatment Fibrinogen serum concentrations, NLRs and PLRs were highest in patients with TCs and advanced tumor stages. High pretreatment Fibrinogen serum concentration (≥452.5 mg/dL) was significantly associated with worse cause specific survival (CSS; = 0.001) and freedom from recurrence (FFR; = 0.043), high NLR (≥4.0) with worse FFR ( = 0.008), and high PLR (≥136.5) with worse CSS ( = 0.032). Longitudinal analysis revealed that compared to patients without tumor recurrence, patients with tumor recurrence had significantly higher NLR (11.8 ± 4.0 vs. 4.70 ± 0.5; = 0.001) and PLR (410.8 ± 149.1 vs. 228.3 ± 23.7; = 0.031).

Conclusion: Overall, Fibrinogen serum concentrations, NLRs, and PLRs were associated with higher tumor stage, more aggressive tumor behavior, recurrence, and worse outcome. Prospective multicenter studies of the diagnostic and prognostic potential of Fibrinogen, NLR, and PLR are warranted.

Methods: This retrospective analysis included 122 patients with TETs who underwent surgical resection between 1999-2015. Fibrinogen serum concentrations, NLRs, and PLRs were measured in patients preoperatively, postoperatively, and later during follow-up. These markers were analyzed for association with several clinical variables, including tumor stage, tumor subtype, FFR, and CSS and to evaluate their prognostic and diagnostic impact for detecting tumor recurrence.
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http://dx.doi.org/10.18632/oncotarget.25076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955144PMC
April 2018

CCL2 is a KIT D816V-dependent modulator of the bone marrow microenvironment in systemic mastocytosis.

Blood 2017 01 16;129(3):371-382. Epub 2016 Nov 16.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. As found in other myeloproliferative neoplasms, increased production of profibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the proangiogenic cytokine CCL2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNA interference-mediated knockdown of KIT reduced expression of CCL2. We also found that nuclear factor κB contributes to KIT-dependent upregulation of CCL2 in mast cells. In addition, CCL2 secreted by KIT D816V mast cells was found to promote the migration of human endothelial cells in vitro. Furthermore, knockdown of CCL2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in vivo compared with CCL2-expressing cells. Finally, we measured CCL2 serum concentrations in patients with SM and found that CCL2 levels were significantly increased in mastocytosis patients compared with controls. CCL2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migration and angiogenesis in SM. CCL2 expression correlates with disease severity and prognosis. Whether CCL2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.
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http://dx.doi.org/10.1182/blood-2016-09-739003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115851PMC
January 2017

Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling.

Cell Rep 2016 10;17(2):596-608

Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge CB2 0QQ, UK. Electronic address:

Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK-) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK- ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.
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http://dx.doi.org/10.1016/j.celrep.2016.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066089PMC
October 2016

Impact of white blood cell counts at diagnosis and during follow-up in patients with essential thrombocythaemia and prefibrotic primary myelofibrosis.

Br J Haematol 2017 10 19;179(1):166-169. Epub 2016 Jul 19.

Division of Haematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/bjh.14202DOI Listing
October 2017

Lymphovascular invasion of tumor cells in lymph node metastases has a negative impact on survival in esophageal cancer.

Surgery 2016 08 14;160(2):331-40. Epub 2016 Apr 14.

Department of Pathology, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Lymph node metastases constitute a strong prognostic factor in esophageal cancer. Nevertheless, the mechanisms and relevance of further spread of tumor cells from these already established metastatic sites have not been studied in this disease. The aim of this study was to investigate lymphatic vessel invasion (LVI) of tumor cells and lymphatic microvessel density in lymph node metastases in a large cohort of patients with node-positive esophageal cancer.

Methods: A total of 120 patients with node-positive esophageal cancer (67 adenocarcinomas, 53 squamous cell carcinomas) and radical esophagectomy were analyzed for LVI and lymphatic microvessel density in primary tumors and lymph node metastases using D2-40 immunostaining. In 18 patients, additional tissue from distant metastases was available.

Results: LVI was present in 52.1% (62/119) of primary tumors, 52.5% (63/120) of lymph nodes, and 22.2% (4/18) of distant metastases. LVI in primary tumors strongly correlated with LVI in lymph node metastases (P < .05), regardless of histologic subtype. In univariate analysis, LVI in lymph node metastases was associated with shorter disease-free survival and overall survival in all tumors and in adenocarcinomas, and with shorter disease-free survival in squamous cell carcinomas (P < .05, log-rank test). Multivariable analysis revealed LVI in lymph node metastases as an independent prognostic factor for disease-free survival in the whole cohort and for disease-free and overall survival in patients with adenocarcinomas (P < .05, Cox regression).

Conclusion: LVI in lymph node metastasis is a significant prognostic factor in metastatic esophageal carcinoma and seems to play a relevant role in disease progression.
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http://dx.doi.org/10.1016/j.surg.2016.02.034DOI Listing
August 2016

Multicenter Evaluation of a Novel Automated Rapid Detection System of BRAF Status in Formalin-Fixed, Paraffin-Embedded Tissues.

J Mol Diagn 2016 05 24;18(3):370-377. Epub 2016 Feb 24.

Institute of Pathology, Charité-Universitaetsmedizin Berlin, Berlin, Germany.

The mutated BRAF oncogene represents a therapeutic target in malignant melanoma. Because BRAF mutations are also involved in the pathogenesis of other human malignancies, the use of specific BRAF inhibitors might also be extended to other diseases in the future. A prerequisite for the clinical application of BRAF inhibitors is the reliable detection of activating BRAF mutations in routine histopathological samples. In a multicenter approach, we evaluated a novel and fully automated PCR-based system (Idylla) capable of detecting BRAF V600 mutations in formalin-fixed, paraffin-embedded tissue within 90 minutes with high sensitivity. We analyzed a total of 436 samples with the Idylla system. Valid results were obtained in 421 cases (96.56%). Its performance was compared with conventional methods (pyrosequencing or Sanger sequencing). Concordant results were obtained in 406 cases (96.90%). Reanalysis of eight discordant samples by next-generation sequencing and/or pyrosequencing with newly extracted DNA and the BRAF RGQ Kit confirmed the Idylla result in seven cases, resulting in an overall agreement of 98.57%. In conclusion, the Idylla system is a highly reliable and sensitive platform for detection of BRAF V600 mutations in formalin-fixed, paraffin-embedded material, providing an efficient alternative to conventional diagnostic methods, particularly for routine diagnostics laboratories with limited experience in molecular pathology.
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http://dx.doi.org/10.1016/j.jmoldx.2015.12.005DOI Listing
May 2016

Cooperation of ETV6/RUNX1 and BCL2 enhances immunoglobulin production and accelerates glomerulonephritis in transgenic mice.

Oncotarget 2016 Mar;7(11):12191-205

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

The t(12;21) translocation generating the ETV6/RUNX1 fusion gene represents the most frequent chromosomal rearrangement in childhood leukemia. Presence of ETV6/RUNX1 alone is usually not sufficient for leukemia onset, and additional genetic alterations have to occur in ETV6/RUNX1-positive cells to cause transformation. We have previously generated an ETV6/RUNX1 transgenic mouse model where the expression of the fusion gene is restricted to CD19-positive B cells. Since BCL2 family members have been proposed to play a role in leukemogenesis, we investigated combined effects of ETV6/RUNX1 with exogenous expression of the antiapoptotic protein BCL2 by crossing ETV6/RUNX1 transgenic animals with Vav-BCL2 transgenic mice. Strikingly, co-expression of ETV6/RUNX1 and BCL2 resulted in significantly shorter disease latency in mice, indicating oncogene cooperativity. This was associated with faster development of follicular B cell lymphoma and exacerbated immune complex glomerulonephritis. ETV6/RUNX1-BCL2 double transgenic animals displayed increased B cell numbers and immunoglobulin titers compared to Vav-BCL2 transgenic mice. This led to pronounced deposition of immune complexes in glomeruli followed by accelerated development of immune complex glomerulonephritis. Thus, our study reveals a previously unrecognized synergism between ETV6/RUNX1 and BCL2 impacting on malignant disease and autoimmunity.
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http://dx.doi.org/10.18632/oncotarget.7687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914278PMC
March 2016

Incidence of intensive care unit admission, outcome and post intensive care survival in patients with diffuse large B-cell lymphoma.

Leuk Lymphoma 2016 08 13;57(8):1831-8. Epub 2016 Jan 13.

a Department of Medicine I, Intensive Care Unit 13i2 , Medical University of Vienna , Vienna , Austria ;

Some patients with diffuse large B-cell lymphoma (DLBCL) require intensive care unit (ICU) admission prior to or during chemotherapy. We analyzed all unscheduled ICU admissions in 331 consecutive patients (18-93 years) with newly diagnosed DLBCL. Thirty-seven patients (11.2%) required ICU treatment primarily due to hemodynamic (37.8%) or respiratory failure (24.3%). Bulky disease and high IPI score were predictive of ICU admission in the early course. ICU and hospital survival was 75.7% and 70.3%, respectively. Overall survival in ICU patients with newly diagnosed DLBCL was worse compared to non-ICU-patients (40.7% vs. 72.7% at two years). However, survival of high-risk patients (IPI 3-5), continuous complete remission, and disease-free survival did not differ. Post-ICU survival was poor in patients with relapsed/refractory DLBCL (0.1-10 months). Our observations favor unrestricted ICU support in DLBCL patients undergoing first-line therapy. ICU referral of patients with refractory/relapsed disease must be evaluated in the context of the hematologic prognosis.
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http://dx.doi.org/10.3109/10428194.2015.1106537DOI Listing
August 2016

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.

Nat Commun 2016 Jan 12;7:10087. Epub 2016 Jan 12.

Department of Pathology, University of Cambridge, Cambridge CB21QP, UK.

Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy.
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http://dx.doi.org/10.1038/ncomms10087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729925PMC
January 2016

Impact of Single or Combined Genomic Alterations of TP53, MYC, and BCL2 on Survival of Patients With Diffuse Large B-Cell Lymphomas: A Retrospective Cohort Study.

Medicine (Baltimore) 2015 Dec;94(52):e2388

From the Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria (A-IS, CK, IS-K, BS, KW, BM, LM); Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (CS, KV, UJ, EP); Division of Palliative Care, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (EKM); Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (DS); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (DS); Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, Veterinary University of Vienna, Vienna, Austria (VS); Division of Oncology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (MR); Institute of Pathology and Bacteriology, Wilhelminenspital, Vienna, Austria (AC); Portuguese Institute of Oncology, Haematology Unit, Lisbon, Portugal (MGdS); and Portuguese Institute of Anatomical Pathology, Lisbon, Portugal (JC).

MYC and BCL2 translocations as well as TP53 deletion/mutation are known risk factors in diffuse large B-cell lymphoma (DLBCL) but their interplay is not well understood.In this retrospective cohort study, we evaluated the combined prognostic impact of TP53 deletion and mutation status, MYC and BCL2 genomic breaks in tumor samples of 101 DLBCL patients. The cohort included 53 cases with MYC rearrangements (MYC+).TP53 deletions/mutations (TP53+) were found in 32 of 101 lymphomas and were equally distributed between MYC+ and MYC- cases (35.8% vs. 27.1%). TP53+ lymphomas had lower responses to treatment than TP53- (complete remission 34.4% vs. 60.9%; P = 0.01). TP53 alteration was the dominant independent prognostic factor in multivariate analysis (P = 0.01). Overall survival (OS) varied considerably between subgroups with different genomic alterations: Patients with sole MYC translocation, and interestingly, with triple MYC+/BCL2+/TP53+ aberration had favorable outcomes (median OS not reached) similar to patients without genomic alterations (median OS 65 months). In contrast, patients with MYC+/BCL2+/TP53- double-hit lymphomas (DHL) (28 months), MYC+/BCL2-/TP53+ lymphomas (10 months) or sole TP53 mutation/deletion (12 months) had a poor median OS. Our findings demonstrate differences in OS of DLBCL patients depending on absence or presence of single or combined genetic alterations of MYC, BCL2, and TP53. Cooccurrence of TP53 and BCL2 aberrations ameliorated the poor prognostic impact of single TP53+ or BCL2+ in MYC positive patients.This pilot study generates evidence for the complex interplay between the alterations of genetic pathways in DLBCL, which goes beyond the concept of DHL. The variable survival of DLBCL patients dependent on single or combined alterations in the TP53, MYC, and BCL2 genes indicates the need for comprehensive genomic diagnosis.
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http://dx.doi.org/10.1097/MD.0000000000002388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291628PMC
December 2015

The role of AP-1 and epigenetics in ALCL.

Front Biosci (Schol Ed) 2015 Jun 1;7:226-35. Epub 2015 Jun 1.

Clinical Institute of Pathology, Medical University of Vienna, Wahringer Gürtel 18-20, A-1090 Vienna, Austria,

Anaplastic large cell lymphoma (ALCL) is an aggressive, highly proliferative, T-cell lymphoma with increasing incidence worldwide. Anaplastic Lymphoma Kinase (ALK) fusions occur in about 50% of all cases. Most ALK positive cases of ALCL harbor the t(2;5) translocation that leads to expression of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK). NPM-ALK induces a variety of oncogenic signaling pathways that lead to malignant transformation of T-cells via Activator Protein-1 (AP-1), STAT3 and other (transcription) factors. In addition to the commonly known AP-1 activators Mitogen-Activated Protein Kinases (MAPKs), there are other signaling pathways, such as PI3K/mTOR/AKT, which are implicated in AP-1 activation/expression in ALCL. The AP-1 factor JUNB was shown to drive ALCL proliferation and the expression of the characteristic ALCL Ki-1 antigen, CD30. cJUN and JUNB target PDGFRB, thereby leading to tumor progression and dissemination. Furthermore, aberrant gene expression in ALCL is frequently accompanied by changes in epigenetic regulatory mechanisms, such as DNA methylation patterns. Here, we discuss the role of AP-1 in the pathogenesis of ALCL and provide an overview of pathological epigenetic changes in ALCL cells.
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http://dx.doi.org/10.2741/S436DOI Listing
June 2015

Transformed mycosis fungoides: bridging to allogeneic stem cell transplantation with brentuximab vedotin.

Leuk Lymphoma 2016 19;57(1):206-8. Epub 2015 Jun 19.

a Department of Internal Medicine I , Division of Hematology and Hemostaseology, Medical University of Vienna , Vienna , Austria.

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http://dx.doi.org/10.3109/10428194.2015.1044748DOI Listing
October 2016
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