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New therapies for myeloproliferative diseases based on multi-stage and -system analyses of the haematopoietic stem-cell niche

Periodic Reporting for period 2 - StemNicheOnWaveCrest (New therapies for myeloproliferative diseases based on multi-stage and -system analyses of the haematopoietic stem-cell niche)

Reporting period: 2017-03-01 to 2018-08-31

Until recently, it was believed that cancer was only driven by changes inside cells: genes become mutated, cells grow uncontrolled, and a tumour arises. However, recent evidence indicates that the surrounding environment where tumour cells live also plays an important role in cancer. Susceptibility factors, different from the mutations, might also influence cancer progression. This project aims at understanding how the tumour cells interact with the specialised environment where these cells reside, and how we can target these interactions to improve patient care.

In a group of bone marrow disorders known as myeloproliferative neoplasms, a defective gene causes hematopoietic stem cells (HSCs) to make too many blood cells. This increases the risk of formation of blood clots, leading to increased rates of cardiovascular diseases and stroke. As the blood cells build up, the disease worsens, sometimes causing tissue degeneration in the form of myelofibrosis or even evolving into cancer. Myelofibrosis is a serious condition that disrupts the normal production of blood cells. It is characterised by bone marrow scarring, leading to severe anaemia, weakness, fatigue, enlarged spleen and liver, and high risk of transformation into cancer, associated with reduced life expectancy. The only real cure is a bone marrow transplant, but this is not feasible in many patients due to the toxicity of this procedure in these patients. Therefore, these diseases are generally not cured, they increase in the elderly and represent a large socio-economical burden.

Studying the process in mice, our team discovered that the mutant HSCs produced an abundance of small inflammatory proteins called cytokines that were damaging nearby neurons. This damage, in turn, prevented the nerves from activating other cells that help regulate HSCs. This damage increased the potential for myeloproliferative neoplasms. When we added an analog of the neurotransmitter adrenaline to compensate for the damaged neurons’ inability to fire, we observed tissue regeneration and improvement of myelofibrosis. Similar results have been observed in a phase II clinical study performed in collaboration with the Swiss Cancer Group.

To be able to treat this damage to neighbouring cells we first need to understand how these neighbours interact with normal and mutated HSCs. Therefore, one first goal of this project is aimed at understanding how this partnership of HSCs and their neighbouring cells is established and to identify pathways that regulate these interactions. A second goal is to study niche alteraltions in myeloproliferative diseases and manipulate these pathways for therapeutic purposes. A third goal exploits another potential susceptibility factor that might influence myeloproliferative disease progression: HSC regulation by sex hormones. Overall, these aims will increase our knowledge of the regulation of the HSC niche and how to target it therapeutically.
Most efforts at treating myeloproliferative neoplasms are focused on blocking the mutation in HSCs. We have been studying alternative complementary ways to treat these diseases based on possible susceptibility factors. One factor might be the microenvironment where leukaemic cells reside, which maintains these cells and can eventually protect them from current therapies, leading to cancer re-appearance. Understanding how mutated blood cells alter their microenvironment requires previous dissection of how normal HSCs interact with their niche. Blood cells are produced in the bone marrow, which contains two distinct adult stem cell types: haematopoietic stem cells (HSCs), that generate all blood and immune cells, and mesenchymal stem cells (BMSCs), thought to form the skeleton. During this project we have investigated mechanisms by which some BMSCs regulate the behaviour of normal HSCs. One of these mechanisms involves the nervous system: the nerves activate BMSCs that, in turn, regulate HSCs. The work performed shows that the peripheral nervous system indirectly controls the growth and the migration of HSCs in different bone marrow locations. This might allow the organism to fine-tune HSC behaviour according to the organism’s demands. The nervous system would also respond to stress situations by activating HSCs in one compartment but simultaneously protecting the overall HSC pool from exhaustion by enforcing the opposite effect in a different compartment. Interestingly, the work performed indicates that peripheral neurons and their supporting cells share a common developmental origin with some of these BMSCs that are important to regulate HSCs. Therefore, this inter-dependence seems to be built among cells that share a common ancestry.

Myeloproliferative neoplasms have a higher incidence of becoming acute myelogenous leukaemia (AML), a disease with very bad prognosis and resistance to therapy. The work performed shows that one mechanism that allows leukemic cells to survive and resist therapy involves their interaction with the microenvironment. Particularly, we have found that leukaemic cells instruct some BMSCs to provide them with energy and defence against excessive levels of damaging reactive oxygen species generated during the rapid growth of leukaemia. This might facilitate devising new complementary treatments for leukaemia that target the microenvironment that maintains and protects leukaemic cells.

Another susceptibility factor in leukaemia is gender. Blood cancers are more common in men than in women, but it has not been clear why this is the case. The studies performed provide an explanation, revealing that female sex hormones called oestrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to blood cancers. Moreover, findings in mice with myeloproliferative neoplasms suggest that a drug called tamoxifen, which targets oestrogen receptors and is approved for the treatment of breast cancer, might also be beneficial for the treatment of myeloproliferative neoplasms. In mice, tamoxifen treatment was able to restore normal levels of programmed cell death (a quality control mechanism) in mutant cells. A clinical study to test and understand the effects of tamoxifen in these human diseases is under way.
Most of the treatments for myeloproliferative neoplasms are based on targeting the mutation in HSCs. We are developing an alternative approach focused on external susceptibility factors: gender and the microenvironment. The project progress goes beyond the state of the art in this field. It was previously known that normal and leukaemic HSCs are regulated by a specialised microenvironment (“niche”) which contributes to maintain them in a slowly proliferative state that makes them more resistant to chemotherapy, a major cause of tumour regrowth. It was also known that BMSCs stand out of this microenvironment as key cells regulating normal and malignant HSCs. However, it was previously believed that the same cells that form the skeleton also contribute to the establishment of the HSC niche in the bone marrow. It was also thought that the specific mutations found in leukaemic stem cells autonomously caused myeloproliferative diseases and therefore represented the only possible therapeutic targets. The work performed builds on our own findings that challenge current dogmas in this field: the identification of different BMSCs with non-overlapping functions (skeletal and HSC niche maintenance) in the foetal bone marrow. We have expanded the functional association of BMSCs with sympathetic nerves, that we reported previously, to the neural regulation of HSC growth and migration in separate bone marrow compartments through different mechanisms. Our discovery of external signals (oestrogens, sympathetic nervous system) that can influence the progression of myeloproliferative neoplasms is now being tested in two independent Phase-II clinical studies with additional tagged research. Overall, these studies will increase our understanding of the HSC niche regulation and might pave the way for new complementary therapeutic strategies to treat mostly incurable myeloproliferative diseases.