The Era of Targeted Therapy for Acute Myeloid Leukemia - Episode 2

The Microenvironment and Epigenetics in AML


Harry Erba, MD, PhD: There’s more to the biology and pathogenesis of leukemia than just the mutational profile in the leukemic cell itself. It’s the microenvironment of the disease as well. Eunice, do you want to talk about that?

Eunice Wang, MD: I think that in the past when we’ve studied leukemia, we’ve done so in a very preclinical way by taking the cells and putting them in cell culture dishes and adding drugs. Now, we’ve developed a lot of agents that way, but we think we plateaued in our ability to kill leukemia cells in that way, because sometimes our results in the cell culture dish didn’t translate to what we saw in patients. It’s important to remember that in a patient, the leukemia cells are living within specified niches in the bone marrow microenvironment. And those niches are very important.

There are a significant amount of data that the adherence or adhesion of leukemia cells to endothelial cells within the bone marrow niche can mediate chemoresistance—just that particular microenvironment’s leukemic cell interaction. There are obviously a lot of emerging data that the microenvironment within the bone marrow space is inhabited not only by leukemia cells or normal hematopoietic cells, but also immune cells, and the leukemia cells are altering the local microenvironment to make it a more immunosuppressed environment. That is important for the progression of the disease.

There are interactions even within terms of oxygen delivery. A patient’s samples are isolated in the laboratory, but a patient’s leukemia cells within the microenvironment are within an inherently hypoxic microenvironment. The metabolic and mitochondrial changes that those cells undergo to allow them to persist and thrive within a hypoxic bone marrow microenvironment are very important. So, I think that it’s an emerging field, and as we’ll be talking about shortly, there are developments of novel therapies manipulating the microenvironment, manipulating adhesion, and manipulating the immune microenvironment that are now starting to yield actual therapeutic implications.

Harry Erba, MD, PhD: Now, some of these mutations that we talked about will inactivate very important genes in normal bone marrow function. But, you can also inactivate genes by epigenetic modulation, and that may be important as well in the pathogenesis. Jorge, do you want to discuss that?

Jorge E. Cortes, MD: Absolutely. I think that’s very important, because it underscores how complex the biology is becoming as we understand these different elements, as we’ve been discussing now. It’s not only whether there’s a gene that’s mutated in the microenvironment, but also how the expression of certain genes is regulated. Little by little, we’ve understood that this is very tightly regulated in normal hematopoiesis and very frequently dysregulated in these leukemia cells. And that leads to their abnormal behavior and the development of these phenotypes, which makes it much more difficult to control because we need to attack it from different perspectives.

We have learned that there are ways to regulate the expression of the genes, and that’s what these epigenetic modulators do. It has allowed us to understand how we can try to control this expression, or lack of expression. If you silence a gene that is an oncosuppressor gene, well then that’s not a good thing, and they developed that. We’ve also learned that some of the mutations that we’ve been detecting in some of these patients actually do not activate a certain pathway, but precisely affect the epigenetic regulation of other pathways that become very important. So, sometimes you can regulate that directly, sometimes indirectly, for these mutations, etc.

I think we still need to understand a little bit better how you affect this. Of course, now we’re starting to be able to manipulate the epigenetic expression of the genes, but it’s a global phenomenon. It’s something where you silence it, but we don’t know what genes we can control and we don’t know how we can regulate some genes.

Eunice Wang, MD: The precision’s not there.

Jorge E. Cortes, MD: Exactly. So we still have a ways to go, but at least we know now that it is an important phenomenon that needs attention, and we’re starting to work on that. Now we need to understand it better and refine it more to regulate what we want to regulate and not touch things that we may end up having a negative effect on if we do that.

Harry Erba, MD, PhD: Yes, and a few years ago Ken Figueroa actually divided the patients by their methylation pattern into different prognostic groups. There was some overlap between the fusion genes and some of the genetics, but not perfect overlap. But, you’re right. How can we intervene to overcome this and improve the outcome of patients? I’m still not certain how we can do that.

Transcript Edited for Clarity