MPN Workshop of the Carolinas 2025 | The role of HMGA1 in driving MPN progression

So my laboratory has been studying a remarkable protein and gene called HMGA1. It stands for high mobility group A1 protein or gene, and they were named because they’re small proteins. Therefore, they have high mobility in gels and they have the name high mobility group. And they have A because they bind to AT-rich regions in chromatin. And what we’ve discovered is that these remarkable proteins bind to our genome and open and close different regions to activate gene networks that drive MPN progression. So these genes and proteins are normally abundant in our stem cells. They’re also abundant in developing embryos. And when, for example, blood stem cells acquire a mutation like JAK2 in MPN, HMGA1 gets upregulated and amplified. And then it turns on pathways that we have identified as required to drive progression, both in cell-based models and in mouse models. So my talk focused on these genes and proteins during MPN progression. 

We had the opportunity to look at single-cell transcriptomes in patient samples. So we looked at CD34 cells, which are the stem and progenitors from JAK2-mutant MPN patients. And what we found in these single cells is that those stem and progenitors, which harbor the JAK2 mutation, upregulate HMGA1. So the stem cells that have the mutation amplify HMGA1 and overexpress it, whereas the stem cells lacking the mutation had levels that were more similar to normal hematopoietic stem cells. And the other thing that we’ve shown from a number of different cohorts looking at bulk sequencing, sometimes older microRNA platforms, and sometimes validated with quantitative PCR, we showed and published that with MPN progression, levels go up higher. So for instance, if a patient has a more chronic phenotype like PV or ET, levels tend to be higher than what we would see in normal blood stem cells. But when they progress to myelofibrosis, levels go up. And then finally, when they progress to acute myeloid leukemia, levels are highest. So that got us very intrigued in whether or not they could actually be playing a role in pushing progression. And so we’ve done a number of lab-based studies to delineate its function, and we found some pretty remarkable roles in driving progression using various experimental models.

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