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ISAL 2025 | A study investigating the metabolic features of chemotherapy-resistant AML cells
Christina Mayerhofer, MD, Harvard University, Cambridge, MA, comments on a study investigating the metabolic features of chemotherapy-resistant acute myeloid leukemia (AML) cells. The study found that branched-chain amino acids (BCAAs) are upregulated in these cells, and that OGFOD1, a dioxygenase that affects codon-anticodon pairing, plays a crucial role in regulating protein synthesis in these cells. By knocking out OGFOD1 in AML cells, Dr Mayerhofer found that protein synthesis decreased and animal survival improved, supporting the hypothesis that OGFOD1 helps AML cells survive during metabolic stress. This interview took place at the 19th International Symposium on Acute Leukemias (ISAL XIX) in Munich, Germany.
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Transcript
We picked acute myeloid leukemia, AML, as a model because with chemotherapy, most patients respond usually very well, but there’s a high risk of relapse. So we were then asking what are the metabolic features of these chemo-resistant cells, and we used patient-derived xenograft, PDX, and mouse models to study that in vivo and applied chemotherapy in these models. And we saw across multiple data sets that branched-chain amino acids, BCAAs, valine, leucine, and isoleucine were changed...
We picked acute myeloid leukemia, AML, as a model because with chemotherapy, most patients respond usually very well, but there’s a high risk of relapse. So we were then asking what are the metabolic features of these chemo-resistant cells, and we used patient-derived xenograft, PDX, and mouse models to study that in vivo and applied chemotherapy in these models. And we saw across multiple data sets that branched-chain amino acids, BCAAs, valine, leucine, and isoleucine were changed. And when we then performed targeted measurement, we saw in most of the models that they were actually upregulated. Since these are essential amino acids, we could just restrict the mice with BCAA-free diets. And when we then combined BCAA-free diets and chemotherapy, we actually saw that this resulted in improved survival and lower bone marrow burden of the acute myeloid leukemia. We found that BCAAs were not used for energy generation, so we assumed they must be important for protein production. So we then went ahead and measured protein synthesis by OPP incorporation in vivo. And very unexpectedly, leukemia cells upregulated protein synthesis in the absence of BCAAs with chemotherapy. We had initially assumed that mTOR and protein synthesis must be lower in this setting. So we really wanted to follow up and performed ribosome sequencing to study the translation of these cells. And we found that ribosome proteins, including OGFOD1, were increased. So OGFOD1 is a dioxygenase that acts as a metabolic stressor. It hydroxylates the small ribosome close to the decoding center and can affect codon-anticodon pairing. And then when we then knocked out OGFOD1 in AML cells, we found that this decreased protein synthesis and improved animal survival. So our hypothesis at the moment is that OGFOD1 regulates protein synthesis in AML to help these cells survive during metabolic stress.
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