a-chromatin-immunoprecipitation-assay-to-identify-novel-nfat2-target

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant B cell clones and represents the most common leukemia in western ...

University of Tübingen

High-dose chemotherapy with hematopoietic stem-cell rescue is increasingly being used in the treatment of multiple myeloma. Bone marrow and also peripheral blood stem-cell (PBSC) grafts contain measurable quantities of plasma cells, the biological significance of which is unknown.

Myeloma cell contamination of peripheral blood stem-cell grafts can predict the outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation.

Recent findings emphasized a critical role for the Wnt signaling pathway during the early steps of embryogenesis, including the development of the hematopoietic system and cardiac development. To date, the role of Wnt in promoting or inhibiting development of both tissues was discussed controversially, dependent on species and time point of expression. Differentiation of embryonic stem cells (ESC) recapitulates early stages of mammalian development. In the present study, we generated murine ESC lines overexpressing Wnt1 (Wnt1 ES). When induced to differentiate toward the cardiomyocytic lineage, Wnt1 ES showed a significant increased ability to generate cardiomyocytes when compared with a control ESC (control ES) line. In addition, Wnt1 ES cells were unable to form hematopoietic cells, whereas development of endothelial cells, a cell type closely associated with blood during embryogenesis, was comparable to control ES. Finally, cardiac differentiation was markedly decreased by the addition of the Wnt antagonist Dkk-1 to the culture medium. These findings suggest that Wnt1 may regulate differentiation of immature mesodermal cells in a tissue-specific manner.

Wnt1 overexpression leads to enforced cardiomyogenesis and inhibition of hematopoiesis in murine embryonic stem cells.

To determine the long-term outcome of patients after allogeneic transplantation of T-cell depleted versus unmanipulated hematopoietic stem cell grafts with respect to incidence of GvHD and overall survival in 50 consecutive patients.

Long-term results after transplantation of CD34+ selected (CellPro) versus unselected peripheral blood progenitor cells (PBPC) from related allogeneic donors.

Klippel-Trénaunay syndrome (KTS) is a rare congenital anomaly characterized by malformation of lymph and blood vessels as well as growth disturbance of soft tissue and bone. The clinical picture is variable and associated with an increased risk of thromboembolic events mediated by intravascular coagulopathy in venous malformations. Here, we report on a male patient with KTS suffering from recurrent deep vein thrombosis (DVT) and life-threatening bleeding due to consumptive coagulopathy. Furthermore, we describe the successful long-term anticoagulant management with rivaroxaban. 

Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Trénaunay syndrome.

Anemia is a common complication of malignancy, which could result from either compromised erythropoiesis or decreased lifespan of circulating erythrocytes. Premature suicidal erythrocyte death, characterized by cell shrinkage and phosphatidylserine (PS) externalization, decreases erythrocyte lifespan and could thus cause anemia. Here, we explored whether accelerated eryptosis participates in the pathophysiology of anemia associated with lung cancer (LC) and its treatment.

Enhanced eryptosis contributes to anemia in lung cancer patients.

Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.

Immune cell infiltrates have proven highly relevant for colorectal carcinoma prognosis, making colorectal cancer a promising candidate for immunotherapy. Because tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here, we comprehensively describe the naturally presented HLA ligandome of colorectal carcinoma and corresponding nonmalignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA class I ligands on colorectal carcinoma and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic colorectal carcinoma-associated pathways, including Wnt, TGFβ, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired colorectal carcinoma and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be overrepresented merely within the colorectal carcinoma ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T-cell repertoire. Overall, these data show that the HLA ligandome reflects cancer-associated pathways implicated in colorectal carcinoma oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived, tumor antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells, might comprise promising candidates for immunotherapeutic applications. Cancer-associated pathways are reflected in the antigenic landscape of colorectal cancer, suggesting that tumor-specific antigens do not necessarily have to be mutation-derived but may also originate from other alterations in cancer cells. .

Mapping the HLA Ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation.

The role of local surgical procedures in patients with metastatic soft tissue sarcoma is still undefined. Few retrospective studies have reported survival benefits for patients with pulmonary metastases after complete surgical resection. Treatment decisions are therefore mainly based on personal experiences rather than on reproducible knowledge.

Article	Year
Myeloma cell contamination of peripheral blood stem-cell grafts can predict the outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation. Journal of cancer research and clinical oncology\| PubMed ID: 15616828	2005
Wnt1 overexpression leads to enforced cardiomyogenesis and inhibition of hematopoiesis in murine embryonic stem cells. Stem cells and development\| PubMed ID: 19422288	2010
Long-term results after transplantation of CD34+ selected (CellPro) versus unselected peripheral blood progenitor cells (PBPC) from related allogeneic donors. Journal of cancer research and clinical oncology\| PubMed ID: 20217128	2010
Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Trénaunay syndrome. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis\| PubMed ID: 24030117	2013
Enhanced eryptosis contributes to anemia in lung cancer patients. Oncotarget\| PubMed ID: 26872376	2016
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia. Nature communications\| PubMed ID: 28970470	2017
Mapping the HLA Ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation. Cancer research\| PubMed ID: 29789417	2018
Impact of surgery in patients with metastatic soft tissue sarcoma: A monocentric retrospective analysis. Journal of surgical oncology\| PubMed ID: 29953623	2018
Long-term remission of refractory Rosai-Dorfman disease after salvage therapy with clofarabine in an adult patient. Annals of hematology\| PubMed ID: 29980874	2018

Hans-Georg Kopp

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