15 June 2020

US researchers have used a novel in vitro model for acute myeloid leukaemia (AML) to reveal potential drug targets and other new insights into the disease.

Using leukaemia stem cells (LSCs) generated in the lab, a team from the Mount Sinai Health System in New York, USA, discovered that these LSCs were particularly dependent on the transcription factor RUNX1 to survive. RUNX1 activates genes that control the development of hematopoietic stem cells.

To generate LSCs to study in the lab, Dr Eirini Papapetrou and colleagues used induced pluripotent stem cells (iPSCs) which had been created from a sample donated by a patient with AML. The team then encouraged these cells to recapitulate haematopoiesis. In doing so, they generated a population of cells enriched with LSCs, which could give rise to the disease when implanted into in mice.

Studying LSCs has traditionally been challenging, as they are difficult to isolate from samples donated by AML patients. Dr Papapetrou explained that their model makes it much easier to isolate and culture leukaemia stem cells over a long period, which means they could obtain them in large numbers for ongoing research.

As part of their work, they identified a 16-gene signature of LSCs, which correlates with patient survival. Of these genes, TSPAN18, which encodes instructions to make tetraspanin 18, is a promising potential drug target. This is because it appears to mediate some of the effects of RUNX1 on LSCs, and is a cell surface protein which could be targeted with antibody or CAR-T cell therapies. 

Details of their study appear in the journal Cell Reports.

Dr Papapetrou said: “We found earlier studies suggesting that RUNX1 expression is a marker of poor prognosis for patients with acute myeloid leukaemia. Our work may now provide an explanation, namely that RUNX1 is required to sustain leukaemia stem cells and thus propagate the leukaemia.

“It's impossible to say at this early stage when or if our work will lead to significant improvements or possibly a cure for acute myeloid leukaemia, but the results we've seen so far are very promising and underscore the tremendous potential in this field.”

 


 

Source:

Wesely J, Kotini AG, Izzo F, Luo H, Yuan H, Sun J, Georgomanoli M, Zviran A, Deslauriers AG, Dusaj N, Nimer SD, Leslie C, Landau DA, Kharas MG, Papapetrou EP (2020) “Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells.” Cell Reports, doi: 10.1016/j.celrep.2020.107688

Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30641-0


 

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