01 March 2021

An anti-diarrhoea drug could help to reverse resistance to chemotherapy in some acute myeloid leukaemia (AML) patients, according to a new study.

Dr Bernd Zeisig, of King’s College London, and colleagues examined the origins of AML stem cells. The exact cell of origin for AML is still controversial, so the team used multiple different models to investigate.

The researchers reconstructed human AML by forcing blood stem cells in cord blood samples to producing fusion genes involving the MLL gene (now known as the KMT2A gene). These fusion genes – such as MLL-ENL and MLL-AF6 – are known driver mutations of AML.

They found that most MLL-rearranged AML stem cells originated from either common myeloid progenitors (CMPs) or hematopoietic stem cells (HSCs). The researchers confirmed these results by transplanting these human cord blood-derived cells into mice, and in samples obtained from people with AML.

Leukaemia cells from HSCs were found to be significantly more resistant to the chemotherapy drugs cytarabine and doxorubicin than CMP-derived cells. The researchers say this was mainly because the HSC-derived cells expressed high amounts of the protein ABCC3.

The researchers then treated primary patient samples and mouse models of treatment-resistant MLL-rearranged AML with fidaxomicin, an FDA-approved anti-diarrhoea drug that inhibits ABCC3. The found that the drug sensitised the cancers to doxorubicin and improved survival in mice.

Senior author Chi Wai Eric So said: “Given that the drug is already used in the clinic for diarrhoea, it is possible to swiftly initiate early phase clinical trials by repurposing this drug for AML patients – in particular those poor prognostic subgroups with few treatment options.”

The study is published in Science Translational Medicine.


Source

Zeisig BB, Fung TK, Zarowiecki M, Tsai CT, Luo H, Stanojevic B, Lynn C, Leung AYH, Zuna J, Zaliova M, Bornhauser M, von Bonin M, Lenhard B, Huang S, Mufti GJ, So CWE. (2021) “Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukaemia.” Science Translational Medicine, doi: 10.1126/scitranslmed.abc4822

 

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