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Awakening leukaemic stem cells to make them sensitive to chemotherapy

Awakening leukaemic stem cells to make them sensitive to chemotherapy


Researchers from the Josep Carreras Leukaemia Research Institute found that inhibiting the hypoxia response in childhood Acute Myeloid Leukaemia tumours help sensitize leukaemic stem cells, those expanding the tumour, to Cytarabine, the standard of choice chemotherapy. Leukaemic stem cells activate the hypoxia system in the bone marrow to endure its natural low oxygen concentration, making them resistant to anticancer drugs. The results, obtained in vitro and in vivo, pave the way towards an efficient new combinatorial treatment for patients, after diagnosis or relapse.

Acute Myeloid Leukaemia (AML) is the most common leukaemia in adults, but a rare disease among children. Despite childhood AML has an incidence of around 7 cases per million in developed countries, with an overall survival around 75%, there is still room for improvement: up to 40% of the children relapse, with roughly a 30% probability of long-term survival.

AML progression relies on a specific subset of very scarce cells called Leukaemic Stem Cells (LSC), found in the bone marrow, that are resistant to standard of choice chemotherapy, such as cytarabine, leading to relapse after an apparently successful treatment. Previous research found that LSC happen to be in a dormant state due to the low concentration of oxygen in the bone marrow (hypoxia conditions) and that could greatly explain their resistance.

In a recent publication at the journal HemaSphere, an official journal of the European Hematology Association, researchers from the Menéndez Lab at the Josep Carreras Leukaemia Research Institute found that treating the tumour cells with an inhibitor of the hypoxia response would sensitize LSC to Cytarabine and help significantly reduce the population of these cancer-promoting cells, both in vitro and in vivo. The research was a joint collaboration between the Menéndez Lab and researchers from other institutions in Spain, France, The Netherlands and Australia.

The team, spearheaded by Dr. Talia Velasco (former member of the Menéndez Lab), used state-of-the-art technology to identify high-risk childhood AML patients and analyse the transcriptional profile of thousands of individual leukaemic cells. The analysis showed that the hypoxia cellular system was overactivated in virtually all leukaemic cells compared with healthy cells. They then tested the sensitivity to cytarabine with and without BAY87-2243, an inhibitor of the hypoxia system, in cultured cells and in real tumours engrafted in specially produced lab mice.

The results showed that the combination of both drugs enhanced the effectivity of the treatment, with significant reductions of leukaemic cells. A few drawbacks should be addressed before the combinatorial approach becomes a reality in the clinic, since the delivery of drugs at the bone marrow is low and the potential interactions should be sorted out before. However, with the drugs already in the market, or very close to it, it should not take too long to figure it out and add a new bullet in the arsenal to fight against childhood acute myeloid leukaemia.

The research was funded thanks to the contributions of the MSCA H2020 program by the EU, the Asociación Española contra el Cáncer and the Deutsche Jose Carreras Stiftung.

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