BETA What is the APOBEC family of proteins?

Apobec refers to a family of proteins that act like genetic editors in our cells, capable of altering our DNA. These enzymes work by changing one building block of DNA, cytosine, into another, uracil, or thymine. While this editing power is crucial for our immune system, helping us fight off viruses. It can also be a double-edged sword. When Apobec activity becomes unregulated, it can lead to DNA mutations, contributing to genomic instability and even cancer. In this Health Tree University video, Dr. Mara explores how the Apobec mutation signature could be used to predict outcomes in multiple myeloma, offering new insight into personalized treatment strategies. What is Apobec? This principle is the aminase. What is the aminase? It's something that changes our DNA. Our DNA is like a code of four letters, A, C, G, T. So you have all these letters for three billion positions. So it's like a string of three billion of these four different letters. And let's say that one letter, because you replicate your DNA, got lost. It happens all the time. Right now, in probably millions of my cells, these mistakes happen. And we have mechanisms that fix these mistakes. So Apobec is part of this big family of the aminase that help potentially to fix the genome or to make it worse. Its function in normal tissue is very obscure. We know it activates in viruses, basically introduce mutation in viruses. The idea is probably to make them altered, so the virus basically is damaged. It can activate some immune response, like in a B cell, introducing for the create more effective antibodies. So in principle, Apobec is something that is good for our body. But what happens is that when you have a cell that is transformed into a non-plastic cell, and it starts to proliferate, Apobec starts what we think, Apobec starts to misbehave. So it's trying to fix as you would do in a normal cell, but by trying to fix something, it actually makes it worse. So it's kind of like you have a fire and you basically drop fuel or gas instead of water. And that's what Apobec does. So instead of fixing the DNA or stopping the tumor, it's actually introducing more mutations. So that's why Apobec is always late in our timing model, because you need first the cell to transform and to start to proliferate, and then Apobec cause the mutations. Why is studying Apobec important in myeloma research? Why Apobec is important for all our discoveries? First, because we think it's present, it's detectable in 90% of patients with diagnosis, and I think it's probably present in all patients. We just don't see it. It might be very hidden in a small subclones. In fact, we do see Apobec in every relapse myeloma. So why is it important? Because smoldering myeloma without Apobec or mGas without Apobec are probably not neoplastic, while Apobec in smoldering, actually those are already tumors. So we have evidence that we will present soon with Mayo Clinic and other partners that patients with smoldering myeloma with Apobec are already tumors. Even if they progress in 10 years or 5 years, those are already tumors. That's one aspect. So it's basically a marker of transformation, which I think is very useful in myeloma because we have strategies of early interception. We have an easy way to detect the smoldering. We just prefer the blood. The second aspect is that we know that the particular group of myeloma, some of them, most of them have MAF or MAFB translocations in the FISH report. They have this so-called hyper Apobec profile. So where main mutational process. So like 50%, 20%, 90% of all the mutations are Apobec only. And these patients have a completely different biology compared to the rest of myeloma. They have a very poor outcome and Dara-Vir, Dara-Tuma doesn't seem to improve this outcome. We think B-Specific might be more effective, but we're still working on the data, so we're not sure. But this is like really a marker of high risk that is still not part of the new IMS guidelines, but is mentioned in the new IMS guidelines together with CroboTripsy. It's written that there are new markers that we will need to integrate in the future. So we still don't have enough data to integrate them, but I think there is already across the community some sort of agreements that patients with those features are usually bad business. The disease of this patient, not the patient, of course. How can Apobec be used to help identify which smoldering myeloma patients will progress and how can it be used to intervene early? The more we learn about how the tumor evolves over time, because myeloma we know it starts 30 years before the diagnosis. So it's a long time and you can get the smoldering 20 years before the diagnosis. So you can get the smoldering one year before the diagnosis because there is no screening, right? We don't screen the population in the US. So people just find out they have a monoclonal protein and it could take 20 years to progress or it could never progress. Or it could progress in six months. So that's kind of like this heterogeneity. I think it's where genomics integrated with the current clinical score like EMWG 2020 are very effective. For example, in our study that we will present soon, all the patients with EMWG high risk, so the patients where we are trying to develop intervention strategies are all genomically transformed. So this patient have a tumor, but the tumor might progress maybe not in two years, maybe in three, five, six, seven. We have a patient that's progressing 15 years and he was already a tumor. You can see all the markers. He has chromotripsis actually. So that's what I'm saying is like the evolution of myeloma is very long, but also create an opportunity because the fact that it stays 15 years stable, it means that the immune system is probably protecting the patient. So if we learn how to engage the immune system against the tumor, the patient may never progress or may never need the therapy. That's for example, the concept of the Aquila trial published by Thanos Dimopoulos and Vincent Reschkumer and colleagues where there are two single agents versus observation provided advantage. I think it's because it boosts this type of immune surveillance that every small thing has. Apobec proteins have a dual role. They are important for immunity and can also contribute to cancer development. Research into Apobec is ongoing with the goal of understanding their complex roles in myeloma developing new therapeutic strategies. 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