IDH2 Mutation Allows Myeloid Differentiation | Jane Liesveld, MD | ASH 2023

Hi, I'm Jean Liesveld from the University of Rochester. I'm a physician who takes care of patients with leukemia. I also do stem cell transplantation. And I'd like to just share with you some results of an abstract that was presented by an MD PhD student who works in the lab of Dr. Laura Kelvey, who's one of my collaborators. And this has to do with some of the manifestations of a mutation that occurs in about 15 to 20 percent of AML patients, and that's in the IDH2 gene. And while this has a lot of treatment implications, there are a lot of manifestations of this mutation that we don't understand. So what has been done in this project is to look at mutated, mirroring cells. And what has been discovered is that not only does this mutation result in changes in how genes are expressed and how they're regulated, but also has implications for metabolism of the AML cells. What happens in some of the cells that carry this mutation is that this is manifested not only at the leukemia stem cell level, but also as cells mature and differentiate. And so in those cells that carry this mutation, some of the later cells like macrophages have defects in how they handle cells that they need to discard in the bone marrow microenvironment. And this can lead to inflammatory changes in the environment and other implications for cell metabolism that will have manifestations, no doubt, in how these patients do, how these cells differentiate, how they create environments that could be conducive to the survival of these mutated cells. So we're just beginning to understand some of these mutations, that they have implications beyond what we initially thought. In this particular mutation, because of defects in what's called the tricyclic acid cycle, there's an accumulation of an oncometabolite, and that, no doubt, is going to have multiple manifestations. So this abstract was just one way to start understanding in a mirroring model that actually was more aligned with MDS versus AML, but many of these patients who have this mutation in MDS will transform to AML. So this is a beginning to look at how this mutation not only affects the what's called epigenetic program in a cell, but also some of the other metabolic and immunologic manifestations of this mutation. And how that will be able to be more effectively targeted in the future remains a source of work to be done in the future. But this is, I think, a theme through ASH is that AML is often associated with aberrancies in how cells handle metabolites, how these cells require different metabolic substrates in order to function well. So we have a lot to learn in this area, but it's an exciting area, and one that I think will have therapeutic implications for our patients in the future.