New models enable deeper research into acute myeloid leukemia
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Researchers at Tisch Cancer Center have created innovative models of acute myeloid leukemia, offering an unprecedented resource for studying this deadly blood cancer, according to a study published in Blood Cancer Discovery.
Researchers developed the models using genetic reprogramming technology to transform blood or bone marrow cells from 15 patients with AML into induced pluripotent stem cells (iPSCs). These cells can mimic the various stages of AML progression and offer a valuable alternative to animal models or immortalized cell lines, which are currently the standard for AML research.
“These have specific limitations — mouse models are limited in that they rely on a different species, with many differences in how leukemia develops, and that limits our understanding,” Eirini Papapetrou, MD, PhD, professor of oncologic sciences and medicine at Tisch Cancer Institute, part of the Tisch Cancer Center, and director of Center for Advancement of Blood Cancer Therapies at Icahn School of Medicine's Institute for Regenerative Medicine, told Healio. “Immortalized cell lines that come from patients with leukemia are also limited in that they typically capture very aggressive, late-stage disease.”
Papapetrou spoke with Healio about the origin of this project, how the new models have performed so far and the potential long-term clinical implications of this project.
Healio: How did you and your colleagues develop these models?
Papapetrou: We set out several years ago to harness iPSC technology, which emerged in about 2006 and 2007. This allows you to take a human cell and reprogram it to obtain a cell line. This is different than classical immortalized cell lines. With iPSCs, the cell is pushed back to an embryonic stage of development. We basically take a human leukemia genome and capture it in this way. This gives us several very distinct advantages — we can have these cells forever and we have unlimited numbers. We can do a lot of things we couldn’t do with patient cells, because they are limited in number. We can create ISO controls using CRISPR and other technologies, or even derive them straight from patients. In this way, we can do functional experiments, drug treatments, multiomics — many things in great depth that we could only do in a limited way with mouse models or cell lines. So, this is a model that takes the patient material and makes it into a tool that we can use for preclinical studies that is robust, reproducible and conducive to controlled experiments, while maintaining the relevance of having come directly from the patient.
In our current study, we wanted to find out how easily we could make these iPSC cell lines from different patients with leukemia. The question that still remained until now was how to make these lines and then differentiate them back to leukemia cells so we can study them, and how similar these leukemia cells are to the original cells we started with.
Healio: How did you conduct this study?
Papapetrou: We started this very carefully, selecting cases where we had enough cells from the patient. We also evaluated the leukemia cells that were made after the process of reprogramming differentiation, which we transplanted into mice to make patient-derived xenografts. We used single-cell technologies to compare the leukemia that came straight out of the patient to the leukemia that comes from our iPSC cell lines. We found that they are remarkably similar, which was very encouraging. That tells us that indeed, we have found a model that reflects a lot of the biology of the disease in the patient.
Healio: What do you expect to be the long-term implications of this research?
Papapetrou: The power of these models is in the way we’re using them currently. Moving forward, of course, we can also learn about the disease mechanisms and how it develops, and we can find vulnerabilities in leukemias. Leukemia is a fairly genetically heterogenous disease. Even though the clinical presentation is very similar, the mutations that drive different cases may have different therapeutic vulnerabilities. We use this to identify new therapeutic targets to drive drug development. In a more immediate sense, we can also use these as preclinical models to test the effects of potential drugs and learn about the determinants of response and resistance. We have some ongoing studies that we hope to publish showing how response is determined to new therapies such as venetoclax [Venclexta; AbbVie, Genentech]. We have some very interesting findings on that. The bottom line is that these are excellent preclinical models that allow us to understand the determinants of drug response and resistance. Moving forward, we also hope to use them to find new targets and develop better drugs.
Healio: Are these models available to researchers at other institutions?
Papapetrou: Yes, they are available and easy to share with appropriate transfer agreements. We are committed to making them available to researchers. There is also quite a bit of interest from industry and drug developers who want to use these to test their existing pipelines of drugs.
For more information:
Eirini Papapetrou, MD, PhD, can be reached at Papapetrou Labs, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1044A, New York, NY 10029; email: eirini.papapetrou@mssm.edu.
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