IMS 2026 | Exploring arginine metabolism and ASS1 status in t(11;14) myeloma

Yeah, so actually what led us to this observation was we had created cyclin D1 knockout cell lines, and when we removed cyclin D1 from 11;14 cell lines, specifically U266, we looked at the consequences of the downstream genes, and we did notice that ASS1 happened to be one downstream gene. So we were curious to know, what is the role of ASS1? And it’s actually important for arginine metabolism. So it’s important for converting citrulline and aspartic acid to argininosuccinate, which then goes on to create arginine. And we were initially curious to know, do all 11;14 subtypes express ASS1, or is it only a subset of them? And so we kind of re-characterized or re-observed that ASS1 is actually part of the CD1 subtype of 11;14 myeloma, which was actually observed about 20 years ago in a blood paper. And so we wanted to understand more precisely the mechanism for what controls ASS1 expression. So what we found was that cyclin D1 appears to be important for elevated ASS1 expression. So when we looked at the cyclin D1 knockout cells, there was a reduction in H3K27 acetylation, which is a marker that’s associated with expression. So when you see that marker, it’s often more likely to be associated with increased gene expression. So we also had access to ATAC-seq, which is a technique that looks for accessibility of various parts of the DNA. So we compare the accessibility from wild-type to knockout cells, and we found that there is increased accessibility of a specific footprint for a transcription factor called ATF4. And so when we knock down ATF4 in the wild-type cells, we see a reduction in ASS1 expression, suggesting that the possibility of cyclin D1 helping to mediate the accessibility of ATF4 to the ASS1 locus and promote increased ASS1 expression. So high expression of ASS1 is associated with arginine production in the cell, and high arginine production is associated with better growth. So we also know that looking at two different patient cohorts, those patients where the plasma cell has high ASS1 expression tend to do more poorly. So there is an association between high ASS1 expression and then presumably in those patients, high arginine production and more poor overall survival outcome. So in terms of the clinical applicability, there are compounds called, for example, ADI-PEG20, which is a compound that is important for degrading arginine. It may not be as important for 11;14 because they’re actually able to produce their own arginine, but most likely other subtypes of myeloma that does not make arginine could potentially be susceptible to the ADI-PEG20 or arginine degrader. So what’s actually fascinating about 11;14 is that there are two main subtypes, the CD1 and the CD2. And the CD1 tends to be more complex, which is data that Francesco Maura has already shown. It’s also interesting that 11;14 can be associated with plasma cell leukemia. So I’m particularly curious to know what are the more aggressive subtypes of 11;14. And one idea could be that those that are able to produce arginine may be the more aggressive subtypes, but that’s something that we still have to determine.

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