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ICML 2025 | The epigenetics of MYD88 wild-type Waldenström’s macroglobulinemia
In this video, Karan Chohan, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses the distinct epigenetic profile of MYD88 wild-type Waldenstrom’s macroglobulinemia (WM), which may underlie the clinical phenotype and poor response to traditional therapies observed in patients with MYD88 wild-type disease. This interview took place during the 18th International Conference on Malignant Lymphoma (18-ICML) in Lugano, Switzerland.
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Transcript
So, MYD88 wild type Waldenstrom’s macroglobulinemia represents about 10% of patients with Waldenstrom’s. And currently we know from the clinical papers that these patients are at higher risk for transformation, and they have poor response to the traditional BTKi-based therapies that we currently use. The paper we have and we’re presenting today is focused on the epigenetics of MYD88 wild type Waldenstrom, specifically the non-coding epigenetics...
So, MYD88 wild type Waldenstrom’s macroglobulinemia represents about 10% of patients with Waldenstrom’s. And currently we know from the clinical papers that these patients are at higher risk for transformation, and they have poor response to the traditional BTKi-based therapies that we currently use. The paper we have and we’re presenting today is focused on the epigenetics of MYD88 wild type Waldenstrom, specifically the non-coding epigenetics. The two aspects we’re interested in are looking at DNA methylation as well as microRNAs and what we did for this project is compare the methylation profile and microRNA profile of patients with wild type disease compared to those who have mutated disease and patients with wild type compared to those who are controls or healthy controls that we saw at Mayo Clinic.
What we found from this project was that firstly, patients who have MYD88 wild type disease have hypermethylation across the genome, and that’s both in coding and non-coding regions. And additionally, when we combine that with pathway analysis, looking at our mRNA expression, we found that several pathways involved in cytokine regulation, intracellular signaling were down-regulated in patients with wild type disease compared to both mutated as well as controls. On our microRNA analysis of patients with wild type disease, we saw that there were several transcripts that were differentially expressed compared to mutated as well as healthy controls. And importantly, what we saw is that one microRNA in particular, MIR-138, which regulates DNMT3A, as well as DOT1L, which are involved in DNA methylation, was differentially expressed as well. So altogether, this shows us that MYD88 wild type Waldenstrom is distinct from those of mutated disease. And epigenetically, especially the non-coding epigenome is different in these patients, which may underlie the biological as well as clinical phenotype we see.
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