Federico Simonetta
Dr
Federico Simonetta,
Hematology Department,
HUG

T-cell immune senescence and exhaustion after allogeneic hematopoietic stem cell transplantation

After allogeneic bone marrow transplantation (BMT), a long lasting immunodeficiency is observed, an abnormality contributing to the risk of cancer relapse and to the susceptibility to infectious complications affecting the quality and quantity of life. The mechanisms of this immune failure are poorly understood despite numerous studies on the subject. Among the cells of the immune system, T lymphocytes play a key role in cancer surveillance and in infection control. After BMT, these T lymphocytes appear exhausted and senescent. Recently, Dr. Simonetta was able to characterize these senescent cells (aging too quickly) in another context (HIV infection), showing that it is possible to identify these cells through the expression of CD57 and the loss expression of a molecule called “eomesodermin”. Preliminary results obtained after BMT seem to suggest the existence of such abnormality in this setting.
This project aims to characterize exhausted and senescent cells, to study their evolution over time and to assess their association with post-allograft complications.

Alessandro Casini
Dr
Alessandro Casini,
Hematology Department,
HUG

Fibrinogen properties and fibrin clot structure in qualitative congenital fibrinogen disorders and correlation with phenotype and genotype

Fibrinogen plays a fundamental role in the normal haemostasis by promoting clot formation, platelet activation and fibrinolysis. Congenital dysfibrinogenaemia is a rare disease characterised by a discrepancy between the functional and the antigen levels of circulating fibrinogen, reflecting the altered functional properties of the molecule due to structural defects. The clinical course of dysfibrinogenaemic patients is highly heterogeneous from absence of symptoms to bleeding or thrombosis. During a post-doc fellowship in the Thrombosis Laboratory of the University of Leeds (Prof Robert Ariëns), Dr Alessandro Casini has learned state-of-the art methodologies to assess fibrin clot properties. The aim of this project, in collaboration with the Marguerite Neerman-Arbez’s group, is to investigate fibrin clot structure from a large series of dysfibrinogenaemic patients in order to better determine the patient’s phenotype and therefore predict the clinical outcomes and tailor the management in specific clinical settings.

Michel Prudent
Dr
Michel Prudent,
Interregional Transfusion CRS

Development of a bioreactor for the study of RBC aging under blood banking conditions

Three thousands red blood cell concentrates are stored for up to 42 days in Switzerland annually. This storage induces the formation of cellular lesions with biological consequences.

In his project, Dr Prudent uses a bioreactor of red blood cells to reproduce the ex vivo aging in a controlled environment, which allows to characterize it. The aim is to improve the safety and the quality of transfused concentrates. The following hypotheses are currently under investigation:

–     Effect of different gas composition (such as the absence of oxygen),

–     Addition of different storage media suitable to improve the storage with anti-oxidant properties, for instance,

–     Addition of rejuvenation media

Dr
Denis Martinvalet, Cellular physiology and metabolism Department, CMU

Mitochondrial morphology in leukemia stem cells vs normal hematopoietic stem cells

Every tumor (leukemia, myeloma, brain tumor) contains a subpopulation of cells with stem cell features called cancer stem cells. These cancer stem cells confer resistance to treatment and are responsible for the disease relapse. Recent work from the team of Dr. Martinvalet have shown that the mitochondria (the cell nuclear plant) of glioma stem cells did not have the same morphology as in differentiated glioma cells and this particular mitochondrial phenotype made these glioma stem cells particularly sensitive to T lymphocytes. Based on similar preliminary results obtained from multiple myeloma, Dr. Martinvalet hypothesizes, that this atypical mitochondrial morphology resulting from the loss of expression of the mitochondrial shaping protein mitofusin 2 observed in glioma stem cells, could be a general feature of cancer stem cells, regardless of their tissue of origin. If Dr. Martinvalet confirms this morphological and functional specificity of cancer stem cell mitochondria, it would open new possibilities to specifically eliminate this subpopulation of cancer stem cells. In the case of leukemia, it would allow the killing of leukemia stem cells, leaving untouched the normal hematopoietic stem cells necessary for the production of normal blood cells.

Stéphane Buhler
Dr
Stéphane Buhler,
Department of genetic and laboratory medicine, immunology and transplantation,   HUG

The clinical relevance of next generation sequencing in hematopoietic stem cell transplantation

A key element in allogeneic hematopoietic stem cell transplantation is the choice of an appropriate donor. Several factors including clinical aspects are usually considered but the main criterion is to find a donor who is HLA (human leukocyte antigen) compatible with the allograft recipient. This is because our immune system and the cells of our body exchange crucial information for self and non-self recognition (pathogens, tumors, grafts) through HLA molecules and because these are almost as diverse as the faces of all human beings. Until recently, the characterization of HLA variability was mostly performed with standard protocols in molecular biology. The advent of new technologies (next generation sequencing) allows exploring the diversity (i.e. the polymorphism) of these genes with a degree of complexity and precision never attained before.

In this project, the Doctors Buhler, Villard and Tiercy propose to correlate this very precise definition of the HLA polymorphism with the clinical follow-up of 300 hematopoietic stem cell allografts performed in Geneva, Basel and Zürich with unrelated donors. This work could allow identifying differences within coding and non-coding sequences of HLA genes that were overlooked as minor in the past but that could have a clinical relevance.

Christelle Borel
Dr
Christelle Borel,
Department of genetic and development medicine, CMU

Single-cell transcriptomic analysis of leukemic stem cells in pediatric patients

Acute lymphoblastic leukaemia (ALL) is the most frequent cancer of childhood and the main cause of cancer-related mortality in children. Evidences suggest that cancer relapse is mainly due to incomplete eradication of residual malignant cells resistant to treatment. The ultimate goal of this research project is to decipher the molecular properties of theseresidual malignant cells using cutting-edge technologies and an interdisciplinary research collaboration. We plan to combine flow cytometry and cell sorting analysis (Prof. Thomas Matthes) with next generation sequencing and genetics analysis on individual cancer cells (Dr Christelle Borel and Prof. Marc Ansari). We propose (i) to sort and isolate leukemic cells from 5 acute leukemia patients collected at the time of diagnosis and after bone marrow transplantation and (ii) to RNA sequence 600 individual cancer cells from these samples in order to provide a comprehensive description of their transcriptomes.
Results from this study might lead to a better understanding of the biology of cancer relapse in ALL patients and could enable the development of novel protocols or pre-emptive therapeutic strategies.