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FP7

LSCMICROENV Result In Brief

Project ID: 294096
Funded under: FP7-PEOPLE
Country: Spain

Towards leukaemia eradication

Targeted therapies for the treatment of cancer are gaining momentum. In an EU study, researchers focused on targeting the tumour microenvironment to eradicate leukaemia.
Towards leukaemia eradication
According to the cancer stem cell model, tumours possess a small subpopulation of cells responsible for cancer initiation and relapse. Leukaemia stem cells (LSC), like normal haematopoietic stem cells (HSC), depend on the interaction with the microenvironment or niche for their self-renewal and maintenance. However, the identity and function of this leukaemic niche still eludes us.

The scope of the EU-funded LSCMICROENV (Regulation of normal and leukaemic stem cells by the microenvironment: role of nestin+ mesenchymal stem cells and humoral signals) project was to investigate the interaction of normal and malignant HSC with the bone marrow microenvironment. The ultimate goal was to develop novel therapeutic strategies for eradicating haematopoietic malignancies that respond poorly to standard treatments.

The work focused on the regulation of HSC by nestin+ mesenchymal stem cells (MSC) and oestrogen hormones. For this purpose, researchers generated transgenic mouse models, where nestin+ cells could be eliminated during the course of MLL-induced acute myeloid leukaemia (AML). They observed that nestin+ stroma cells were required for leukaemia establishment but did not affect the proliferation or survival of leukaemic progenitors. Rather they influenced the self-renewal, protein metabolism and mitochondrial respiration of these cells, and also reduced the outcome of chemotherapy.

In another part of the project, scientists investigated oestrogen receptor signalling on normal and malignant haematopoietic progenitors. Tamoxifen worked as an oestrogen agonist in haematopoietic cells, inducing apoptosis of multipotent haematopoietic progenitors and cell cycle progression in primitive long-term HSC. When used against MLL-induced AML, it enhanced the effect of conventional chemotherapy. Interestingly in myeloproliferative neoplasm (MPN), the effect of tamoxifen alone was more prominent and specific against leukaemia, allowing normal haematopoietic recovery.

Overall, the LSCMICROENV results demonstrate the safety and selectivity of tamoxifen and support its potential use in the clinic. Especially for refractory AML and MPN, the use of oestrogen receptor modulators could find immediate application alone or in combination with conventional therapies.

Related information

Keywords

Leukaemia, microenvironment, leukaemia stem cell, haematopoietic stem cell, nestin, mesenchymal stem cell, oestrogen, tamoxifen
Record Number: 190519 / Last updated on: 2016-11-10
Domain: Biology, Medicine