ISAL 2025 | A study investigating potential treatment targets for AML with the t(8;21) translocation

We start with RUNX1, RUNX1T1. This is the result of the chromosomal translocation t(8;21). This chromosomal translocation defines a group of AML patients. This group of patients usually have a favorable prognosis for the treatment because they respond to standard chemotherapy. However, the challenge within this group of patients is to treat the elderly or the unfit patients, which cannot tolerate high doses of chemotherapy. So, because of that, we try to find other vulnerabilities within this group that we could target in more specific ways. And because of that, we looked into the cytogenetics or the co-occurring mutations of this group of patients and we found that ZBTB7A is frequently and specifically mutated in t(8;21) patients. This is very interesting because ZBTB7A is a transcription factor with repressor activity and it controls differentiation in several branches of hematopoiesis, but also it controls glycolysis. So it’s linking differentiation and metabolism and we know that those two things are related for the normal hematopoiesis. And if we can understand how the block of normal differentiation at the same time that rewiring metabolism happens in those patients, we can find the vulnerability that we can target in therapy. In our work, the challenge to study this model is that primary cells from these patients are hard to cultivate in vitro and also even the PDX from the cells from patients, they don’t engraft very easily. So the challenge to study this group of patients and the development of this disease is to have a system that we can have cells and expand and study the leukemogenesis. So to overcome this challenge, we set out to develop this mouse model in which we are expressing RUNX1-ETO or RUNX1-RUNX1T1, the variant 9A, which is known to generate tumors or to generate leukemia in mice. And we did the knockout of ZBTB7A at the same time. And in this mouse model, we could see that the knockout of ZBTB7A or the loss of ZBTB7A that is mimicking what’s happening in the mutations in the patient, indeed accelerate the development of the disease. And now with this platform we can have a full characterization of this disease and we can use for drug testing in vivo as well as in vitro, ex vivo drug testing with the cells from these mice and going closer to the translation to the clinic one day hopefully.

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