MPN Workshop of the Carolinas 2025 | The potential of HMGA1 as a novel therapeutic target in MPNs and other hematological malignancies

So just to give you a little bit of background about HMGA1 versus 2, they are members of the same family. They’re very highly related. When we look at gene expression data, we tend to see higher levels of A1. So we focused on A1, although there are some very interesting patients who have a translocation involved or some other genetic aberrations involved in HMGA2 that overexpress HMGA2. But when we look across the majority of patients, A1 tends to be highest. And when we’ve done experimental studies to determine its role to see if it really could be a valid target, we found some striking data in our MPN models. So for instance, if we take JAK-mutant AML cell lines that are derived from patients, and we do gene silencing using a variety of approaches, CRISPR or short hairpin RNAs, we find that these cells no longer have the capacity to grow in an uncontrolled fashion and to form clones. And then when we put these cells into mice, we find that HMGA silencing prevents leukemic engraftment and expansion in the mice. So that suggests, at least in this late stage disease, it would be a remarkable target. 

And then we also looked at earlier stage disease. So for example, PV and ET, and their levels are high, but not quite as high as myelofibrosis or AML. And so we, to examine its role in this earlier stage disease, we use mouse models and we have a beautiful JAK2-mutant mouse model that very nicely recapitulates what our patients get. So they get elevations in red cells, elevations in platelets. And over time, like 40 weeks, which is, you know, getting to be quite an older mouse, they develop myelofibrosis with splenomegaly and all of the changes we see in the marrow in our patients. Well, to see if HMGA plays a role in this earlier stage disease, we crossed the JAK-mutant mice and they actually harbor the human JAK mutation, which makes it, I think, even a better model for human disease than using a mouse JAK2 mutation. And what we find is when these mice have just one allele, so 50% of their HMGA genes within their hematopoietic stem and progenitors, and of course, their offspring. They develop a remarkable decrease in their red cells and platelets, so their MPN phenotypes are ameliorated. And then even more remarkably, they do not develop splenomegaly, and they do not progress to myelofibrosis. So we think this would be an incredible therapeutic target. 

And we also know from studies in other tumors, other hematologic malignancies, even solid tumors like pancreatic cancer, we see similar findings, lowering the levels of this gene or protein by only about half prevents tumor progression and prolongs survival in diverse tumor models. Because it’s a transcription factor, there are, of course, challenges to targeting it. It’s a small protein. It’s within the nucleus. So we would need to find, I think, a small molecule inhibitor that disrupts its chromatin binding. But that certainly would be a really impactful discovery. And we’re working to try to define these complexes so we can better understand how we can knock it off chromatin and prevent it from, you know, driving these tumor progression phenotypes.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.