About Decision-making within cells and differentiation entity therapies (DECIDE)
A Marie Curie Initial Training Programme funded by the European Union under the FP7 programme.
The DECIDE Initial Training Network
The DECIDE network sought to advance understanding of normal blood cell development and why primitive cells fail to differentiate in acute myeloid leukaemia (AML). Theteam has used the information gained to develop ways of alleviating the differentiation block in AML and so deliver new agents, including novel vitamin D and retinoid analogues, for use in differentiation therapy. This type of therapy aims to respond to the urgent need to devise milder treatments, especially for older and frailer AML patients.
The network combined the research efforts of prestigious universities and research institutes, Poland’s leading governmental Pharmaceutical Research Institute, and two successful biopharmaceutical companies.It brought together scientists who have made important advances in the fields of haematopoiesis and differentiation therapy and has had both scientific and therapeutic targets. Partners are from the UK, Switzerland, Poland, Ireland, Israel, Spain, and the USA.
DECIDE has trained 12 PhD students. Within the 3 years of their Marie Curie Fellowship, 8 Fellows finished their experimental work and have been awarded their PhD. Two Fellows are awaiting their viva, one is writing her PhD and one Fellow is on a 4 year PhD program.
A clearer picture of blood cell development
One of our main aims has been to contribute towards a better understanding of blood cell development. Textbooks depict this process as a strict hierarchy. The haematopoietic stem cell (HSC) is the apex, chooses either the myeloid or lymphoid pathway and then becomes more lineage-restricted in a stepwise manner through a series of progenitors (HPC). Our pairwise model is very different. Lineage choices are viewed as a continuum, there aren’t underlying branch points and there are particular relationships between each of the cell lineages, based on the sets of potentials seen for various HPC. Work has shown that HSC and HPC have a strong lineage signature. Early Progenitors with Lymphoid and Myeloid potentials have been viewed as a single population of cells - these cells have now been divided into, at least, 3 groups, with a B cell, dendritic or myeloid genetic signature. HSC sub-populations have been identified that express receptors for different cytokines. The cytokines Flt3 ligand (Flt3L) and IL-7 have been viewed as instructing the development of B cells. By contrast, our work has shown that Flt3L provides a proliferative signal and IL-7 a signal for survival to B cell-committed progenitors. Mesenchymal stromal cells (MSCs) are important for haematopoiesis. Experiments to investigate these cells have been largely conducted in conditions of 20% oxygen. The bone marrow is hypoxic and this changes the secretome of MSC. Additionally, MSC are highly radio-resistant, hypoxia increases radio-resistance and Hif-1a plays a key role.
New anticancer vitamins D
Differentiation therapy for cancer aims to drive cancer cells to become mature cells which then die naturally. Two important differentiating agents are 1a,25-dihydroxyvitamin D3 (1,25D) and all-trans retinoic acid (ATRA). An effective therapeutic dose of 1,25D has been difficult to achieve for the treatment of cancer because it also raises the level of calcium in the blood (calcaemic action), potentially leading to cardiac arrest and coma. A second aim has been to syntheses new analogues of 1,25D that have a substantially reduced calcaemic action. New analogues of 1,25D (an1,25D) have been synthesised that are much less calcaemic and more potent than 1,25D against leukaemia and colon cancer cells. The two new an1,25D are very promising candidates for development as anticancer drugs. They still need to be refined further, to enhance drug delivery. All-trans retinoic acid (ATRA), used with arsenic trioxide, has provided a cure for 95% of patients with acute promyelocytic leukaemia. Attention was focussed on whether ATRA can prolong the survival of children with high-risk neuroblastoma. ATRA together with depletion of polyamines (via a polyamine analogue verlindamycin) has been shown to drive terminal differentiation of this cancer and more effectively than either agent alone.
Thirty two papers have been published to date, a paper is under review, 8 papers are in preparation and the book entitled “Diversity, Versatility and Leukaemia”, by Brown and Sanchez-Garcia, appeared in 2016. A highlight is the paper in the Proceedings of the National Academy of Science, USA describing the roles of Flt3 and IL-7 (doi: 10.1073/pnas.1613316113). Special issues of The Journal of Steroid Biochemistry and Molecular Biology (Proceedings of the 18th Vitamin D Workshop) and The International Journal of Molecular Sciences (in honour of Professor Milan R. Uskokovic) contain a series of research articles on our new an1,25Ds and their activities.The Fellows have presented posters and/or given talks at 30 international and local conferences and attended at total of 42 meetings.
There have been 12 main events for the general public, including the British Festival, Lower Silesia (Poland), Big Bang, Think Corner and Fun Palace Science festivals and a Curing Perfect app which examines the benefits of stem cells.