Periodic Reporting for period 4 - StemNicheOnWaveCrest (New therapies for myeloproliferative diseases based on multi-stage and -system analyses of the haematopoietic stem-cell niche)
Reporting period: 2020-03-01 to 2021-02-28
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. 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.
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.