Patient-derived iPSCs faithfully represent the genetic diversity and cellular architecture of AML

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Published: 28 Apr 2023
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Dr Eirini Papapetrou - Icahn School of Medicine at Mount Sinai, New York, USA

Dr Eirini Papapetrou speaks to ecancer about her study which found that patient-derived iPSCs faithfully represent the genetic diversity and cellular architecture of human acute myeloid leukaemia.

This study created a reprogramming method called “Complete Capture of Mutational Burden” (CCoMB).

This method combines comprehensive genetic characterisation of the starting sample and inference of its clonal architecture with large-scale screening of clonally reprogrammed colonies.

Dr Papapetrou explains the aims and objectives of this study.

The results showed very few biological barriers to the reprogramming of AML cells and showed that AML-iPSC-derived leukaemias faithfully mimic the primary patient leukaemias upon xenotransplantation.

In the work we recently presented at the AACR meeting we reported the generation of induced pluripotent stem cell, or iPSC, lines from patients with acute myeloid leukaemia. This is work that has been going on in my laboratory for many, many years, more than a decade now, then we put all this together as a resource for the field of AML and cancer more generally. The motivation behind this study was to try to address some challenges and limitations of existing models of leukaemia and cancer, mainly the fact that immortalised cell lines have been propagated for many, many years and often lose their relevance to the original cancer while, at the same time, on the other hand, primary human cells can only be used for a limited number of experiments because they are limited in numbers and also our ability to culture them ex vivo.

So we used reprogramming technology to capture leukaemia cells from both the bone marrow and the peripheral blood of patients with leukaemia and turn them into induced pluripotent stem cells, or iPSCs. In this way we take a bit of the best of both worlds where we have patient-derived material now in some type of cell line that is not immortalised by strong oncogenes but is maintained through pluripotency and we can then differentiate it back to leukaemias, to haemopoietic cells, and regenerate the leukaemia.

Importantly, what we found was that these leukaemias that we could make after re-differentiating induced pluripotent stem cells back to haemopoietic cells were very, very similar to the original leukaemia cell we took out of the patients. So now this gives us a lot of possibilities. First of all, by doing this we can capture also pre-leukemic stages as well as late leukemic stages and many different stages, clones and subclones, from the patients and study them. Importantly, we can do functional studies with them that we cannot do with primary cells. So we can treat them with drugs, we can do genetic manipulation such as knock-downs, overexpression, knockouts, CRISPR screens, all sorts of screens, barcoding, anything. Any type of experiment that you can do with immortalised cell-lines we can now do with these iPSCs.

So we think that these new models now can really be very valuable for our research but also research by others. We are really committed to share this with the community in making this available through collaborations or material transfer agreements to other researchers who are interested in using these models.

The work we are currently doing and we are planning for the future is using these leukaemia lines for many different types of questions. For example, questions like what determines the drug response or resistance to certain targeted therapies, so specific therapies, and can we learn from this how to better stratify patients who will respond or not based on their genetics.

A second thing is to use this to investigate leukaemia mechanisms – what drives the disease and how we can use this information to learn about new therapeutic targets that we can then use for future drug development.

I want to stress that this is work that has been going on in my laboratory for almost a decade so there are many, many people, past lab members and trainees, who contributed to this. Without them none of this would have happened. It’s a very large commitment and a big amount of work that went into this study. I’m very thankful to everybody who contributed to it, all the past lab members as well as all our funders, that includes a grant from AACR.