Our Latest Research
Dr A Vaglio: Genome-Wide and Epigenome-Wide Association study In
patients with Erdheim-Chester Disease. £50,000.
Aims of the project: Erdheim-Chester disease (ECD) is a rare histiocytosis characterised by proliferation of blood cells called histiocytes, which infiltrate several organs (such as the bone, the heart, the lungs and the brain) and cause irreversible organ damage. The cause of ECD is incompletely understood. Although mutations of genes controlling cell proliferation contribute to disease development, other factors may be involved.
The susceptibility to develop rare diseases such as ECD is usually related to genetic factors,
including gene variants called polymorphisms, together with other inherited variations in the
so-called epigenetic regulation of gene expression.
The present study will analyse the whole genome (the whole genetic information contained
in the cells) of a large ECD patient cohort and of healthy controls, in order to explore
whether gene polymorphisms and epigenetic variants are associated with ECD
The results of this study may clarify the genetic predisposition to ECD, and provide
information regarding the mechanisms used by histiocytes to infiltrate and damage the target
organs; these findings may ultimately help identify proteins or cellular mechanisms that may
be targeted by specific treatments. This approach can also be extended to other histiocytoses
such as LCH, whose genetic landscape is poorly investigated.
Prof. J West: Maximising the use of national electronic health data sources in England to ascertain, register and undertake epidemiologic research in Langerhans cell histiocytosis and Haemophagocytic Lymphohistiocytosis. £49,9356.53.
Aims of the project: The Histiocytic diseases are rare but have potentially very serious consequences in affected individuals.
Researching them is challenging because of:
A lack of accurate information on how new cases are recorded, diagnosed and registered across England;
Incomplete information about the occurrence and natural course of the disease;
Poor understanding of the reasons why these diseases occur; and
The difficulty in identifying large enough numbers of cases to meaningfully answer research
Dr C Booth: Evaluation of quercetin as a novel therapeutic in a murine model of XIAP deficiency. £22382.36
Aims of the project: XIAP Deficiency is one of the genetic causes of haemophagocytic lymphohistiocytosis (HLH), which is a serious life-threatening inflammatory sickness. Patients with XIAP deficiency get sick because their immune system causes too much inflammation. Certain immune system cells over-produce IL-18 and IL-1beta, which are inflammatory proteins. These proteins make patients sick with fevers, low blood counts, HLH, and other problems like inflammatory bowel disease. Patients can die from these problems. Current treatments for XIAP deficiency include steroids and other immune suppression, chemotherapy, or bone marrow transplant, all of which pose serious side effects or risk of death.
New treatments are needed for patients with XIAP Deficiency that don’t have serious side effects or risk of death. We have discovered that quercetin can prevent XIAP deficient cells from making too much IL-18 and IL-1beta. Quercetin is a natural anti-oxidant found in many fruits and vegetables, so it has very few side effects or serious risks. Quercetin may be a good treatment for patients. The aim of this project is to test the ability of quercetin to prevent inflammation and disease in mice with XIAP deficiency to see if a human trial should be done.
Prof. M Collin: UKHR -Registry Research Associate £10,159.73
Development and Expansion of the Rare Histiocytic Disease Registry
2016 The aims of the project were to register patients with rare histiocytic disorders to the International Rare Histiocytic Disorders Registry.
The most important step in understanding rare disease is to collect information about as many patients as possible so that patients, carers and doctors can learn as quickly as possible about common problems and find the best possible treatments.
This project allowed UK patients to become part of this important initiative by funding a research assistant for one day per week to gain the necessary approvals in the UK and to collect and enter information about patients who agree to join.
2017 Prof. Collin, Principal Investigator to the project reported:
“It became apparent that it would be much more cost and time efficient to create a larger entity to encompass both sample and data collection. During the course of the year there have been multiple requests to the lab to provide molecular testing for patients. Creation of a UK-wide Tissue Bank will cover research testing of any patient with histiocytosis, in Newcastle or in any other centre that registers a research project with the registry. The opportunity has arisen to submit data to 2 additional international registries, the ECDGA registry for Erdheim Chester Disease (USA) and the Histiocytic Disorders Registry for Adults (Vienna)”.
2018 Histio UK approve a proposal to continue to fund the UKHR in its expanded capacity of a registry that can coordinate new patient evaluation, participate in international registries and facilitate the use of molecular diagnostic testing.
Histio UK has awarded a further £38,721 to the continuous implementation and development of this Registry.
Publications arising from the grant funding
Four papers have been published on histiocytosis by the Human DC lab. Two using patient material and clinical data enrolled during the project and two review articles:
Hunt, D., Milne, P., Fernandes, P., Bigley, V. & Collin, M. (2017). Targeted treatment of brainstem neurohistiocytosis guided by urinary cell-free DNA. Neurol Neuroimmunol Neuroinflamm, 4, e299.
Milne, P., Bigley, V., Bacon, C. M., Néel, A., McGovern, N., Bomken, S., Haniffa, M., Diamond, E. L., Durham, B. H., Visser, J., Hunt, D., Gunawardena, H. Macheta, M., McClain, K. L., Allen, C., Abdel-Wahab, O. & Collin, M. (2017). Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults. Blood, 130, 167-175.
Collin, M. & Milne, P. (2016). Langerhans cell origin and regulation. Curr Opin Hematol, 23, 28-35.
Egeler, R. M., Katewa, S., Leenen, P. J., Beverley, P., Collin, M., Ginhoux, F., Arceci, R. J. & Rollins, B. J. (2016). Langerhans cell histiocytosis is a neoplasm and consequently its recurrence is a relapse: In memory of Bob Arceci. Pediatr Blood Cancer, 63, 1704-1712.
In 2017 we have committed the following:
£25,000 to Dr. A. van Halteren for:Cost efficient genetic profiling of patients enrolled in LCH1V.
NGS on biopsies on 250 patients enrolled in LCHIV.
£48,000 to Drs. Ehl & Booth for: The Establishment of International HLH Registry.HA/ESID HLH Registry Including 6 UK centres.
£25,000 to Dr.K. Rao for: Retrospective analysis of late effects after Haematopoietic Stem Cell Transplantation in patients with Haemophagocytic Lymphohistiocytosis.Retrospective analysis on long term outcome for patients with HLH who receive BMT.
In 2016 we committed £15,944.34. The aim of the project is to register patients with rare histiocytic disorders to the International Rare Histiocytic Disorders Registry. The most important step in understanding rare disease is to collect information about as many patients as possible so that patients, carers and doctors can learn as quickly as possible about common problems and find the best possible treatments. This project will allow UK patients to become part of this important initiative by funding a research assistant for one day per week to gain the necessary approvals in the UK and to collect and enter information about patients who agree to join.
In 2012 we committed £327,000 over three years to a collaborative project at the Centre for Molecular and Cellular Biology of Inflammation, Kings College London and the Institute of Cellular Medicine, Newcastle, led by Professor Frederic Geissmann and Prof. Matthew Collin.
Summary of results:
Cell autonomous mechanisms in the pathogenesis of Langerhans cell histiocytosis.
Report of Prof.M Collin
Professor Collin has been studying patients with LCH and other related diseases. He has been trying to find out where the cells in LCH lesions come from.
It is known that white cells, including the Langerhans cells in the skin, originate from stem cells in the bone marrow. These stem cells give rise to many types of white cell precursors that gradually develop into the different types of mature white cells found in the blood and tissues. By separating different sorts of white cell from the blood and bone marrow of patients who have the BRAF V600E mutation in their LCH lesions, Prof Collin has been able to determine at what stage in the development of Langerhans cells the mutation occurs.
The results are very important. In some patients, V600E is found only in cells from biopsies of LCH lesions. These patients generally have single system, low risk disease. In contrast, in other patients with V600E in their lesion, the mutation is also found in blood and bone marrow. These patients generally have multi-system high risk disease. The presence of V600E in blood and marrow is therefore an important indicator of the prognosis in a patient.
Other data indicate that LCH may develop from two different cell types in the blood although it is not yet clear whether disease arising from these two cell types differs clinically. Studies of Hairy Cell Leukaemia and Erdheim Chester disease, which also have the V600E mutation, show that these arise from different white cell types, suggesting that additional factors to the mutation determine what sort of disease occurs.
Although many questions about LCH remain, these results will help in the assessment of patients at diagnosis and in future may enable treatment to be tailored to the nature of the disease in each patient.
Cell autonomous mechanisms in the pathogenesis of Langerhans Cell Histiocytosis.
Report of Prof F. Geissmann
This research project had two parts. The first was to extend the finding of Barrett Rollins that the BRAF V600E mutation is present in half of LCH lesions, by searching for other abnormalities in the BRAF cell signalling pathway, which is known to affect cell division, differentiation and secretion. BRAF V600E activates this signalling pathway and is present in several tumours including melanona, thyroid, colon and liver cancers, and some leukaemias, as well as LCH.
We confirmed that BRAF V600E is present in 9/16 LCH lesions, some of which were isolated bone granulomas and others more severe forms of disease. In addition, we found in one patient a different abnormality of BRAF (BRAF 600DLAT), which also activated BRAF signalling. Both mutations were present in the LCH (CD1a+) cells of LCH lesions and absent from patients' blood, as well as from another 58 blood samples from LCH patients at diagnosis or in relapse. These data indicate that activating BRAF mutations are present in lesions from both benign and severe forms of LCH disease and in general absent from peripheral blood. The presence of a BRAF mutation in LCH lesions does not therefore predict the course of disease.
The second part of the project aimed to use transgenic mouse models to help to elucidate whether BRAF V600E expression in macrophages is sufficient to cause LCH, and why LCH is so variable in clinical behaviour. A mouse model might also be useful for testing new therapies.
Different populations of macrophages and dendritic cells are known to develop from distinct precursor populations in the embryo and it seems likely that the BRAF V600E mutation may occur at different stages of maturation of these precursors into mature macrophages or dendritic cells. Therefore models have been constructed with BRAF V600E expressed in different macrophage cell lineages. To enable the gene to be switched on at different stages of development, in some models the gene can be induced by treating the mice with tamoxifen. This treatment also switches on a gene coding for a fluorescent protein so that the BRAF V600E expressing cells can be detected.
Preliminary experiments with these models show that early expression of BRAF V600E in the embryo can affect the viability of the embryos and influence the development of macrophages and dendritic cells. Further work, which is underway, will define the cellular and molecular consequences of BRAF V600E expression in different lineages and at different stages of macrophage and dendritic cell development, providing insights into the role of BRAF V600E in LCH and possibly identifying new therapeutic targets.
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