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Using the Epigenetic Landscape to Define Myeloma

<ѻý class="mpt-content-deck">— New database might help explain progression and resistance, says Rafael Renatino-Canevarolo, PhD
MedpageToday

Multiple myeloma remains an incurable cancer of bone marrow-resident plasma cells that evolve to active disease through therapy resistance. The molecular mechanisms driving progression and refractory disease are poorly understood.

At December's American Society of Hematology (ASH) virtual meeting, data suggested that multiple independent combinations of genetic and epigenetic events alter the balance of master epigenetic regulatory circuitry, leading to genome-wide transcriptional reprogramming.

In this exclusive ѻý video, study author Rafael Renatino-Canevarolo, PhD, a postdoctoral fellow at H. Lee Moffitt Cancer Center and Research Institute in Tampa, discusses the findings.

Following is a transcript of his remarks:

I'm Rafael Renatino-Canevarolo, a postdoc at Moffitt, and my work is called

In our work that's presented at ASH 2020, we studied multiple myeloma, which is a plasma cell cancer. We don't know yet exactly what are the causes that drive disease onset and drug resistance, and the problem is because of that, multiple myeloma is an incurable disease.

By studying a very large cohort of patients that were treated at Moffitt, more than a thousand patients, we're able to see different patterns in gene expression of those cells. And we saw that, for example, pathways related to cell identity were decreased during myeloma onset, while pathways related to metabolism and cell cycle were increased during drug resistance. And later on, we tried to find what could be driving this.

And we found that there were some epigenetic markers and histones that wraps the DNA, and these markers were differentially concentrated during disease stages. We confirmed that in 10 myeloma samples with different disease stages using a technique called single-cell ATAC-seq [Assay for Transposase Accessible Chromatin-sequencing].

And later on, we are able to map those changes to various specific super-enhancer master transcription factors related to plasma cell identity. And we saw that some of them were decreased during myeloma onset and many other ones were increased during drug resistance.

So we came up with this bowtie model in which we could map a lot of mutations and cytogenetic abnormalities with this reprogramming of what we call the epigenome, leading to an increase or decrease of this biological pathway that I mentioned related to myeloma onset and with drug resistance.

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