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ESH CLL 2022 | Richter’s syndrome biology and CLL

In this video, Elisa ten Hacken, PhD, Dana Farber Cancer Institute, Boston, MA, discusses Richter’s syndrome in chronic lymphocytic leukemia (CLL), which is a rare complication of CLL where disease transforms into an aggressive B-cell lymphoma. Dr ten Hacken first highlights the development of novel mouse models that use CRISPR-Cas9 gene editing to monitor transformation and CLL progression. Dr ten Hacken then discusses how these models allow key pathways involved in transformed disease, such as TP53 mutation and mutation in MGA, to be identified. Following this, Dr ten Hacken explains the role of aberrant mixed signaling in transformation and the importance of validating mouse models in human disease. To conclude, Dr ten Hacken explains that further studies are needed to evaluate key functional pathways and potential therapeutic targets in CLL treatment. This interview took place during the 2nd ESH Translational Research Conference on Chronic Lymphocytic Leukemia (ESH CLL), 2022.

Transcript (edited for clarity)

We have been undertaking the effort of developing novel mouse models of Richter’s syndrome. Actually with the intent, initially, of modeling chronic lymphocytic leukemia. We introduced loss of function driver mutations in animals, through CRISPR-Cas9 gene editing; and some of these lesions were key to the transformation into Richter’s syndrome, which represents one of the foremost clinical challenges nowadays, with two to 10% of CLL patients transforming into DLBCL-like histology, which is almost invariably fatal and with very limited therapeutic options...

We have been undertaking the effort of developing novel mouse models of Richter’s syndrome. Actually with the intent, initially, of modeling chronic lymphocytic leukemia. We introduced loss of function driver mutations in animals, through CRISPR-Cas9 gene editing; and some of these lesions were key to the transformation into Richter’s syndrome, which represents one of the foremost clinical challenges nowadays, with two to 10% of CLL patients transforming into DLBCL-like histology, which is almost invariably fatal and with very limited therapeutic options.

Through these mouse models, we were able to highlight key pathways that are involved in transformed disease, and key genetic drivers that are responsible for transformation. These include, of course, the very notable TP53 mutation, which is frequently occurring in high-risk CLL, but also in Richter’s syndrome patients and, importantly, also mutation in MGA, which is a MYC regulator, and CHD2, which is a chromatin remodeler.

We demonstrate through a number of assays and multi-omic analysis, particularly transcriptional, epigenetic, and genomic analysis, we demonstrate that a key pathway that is responsible for transformation, is aberrant mixed signaling similar to other types of lymphomas. And this in turn, leads to vulnerability to MYC inhibitors, but also, mTOR inhibitors, and also PI3 kinase inhibitors. Whereas, quite unexpectedly, we saw a key diminished interferon gamma signaling signature, that is unique to Richter’s and especially to these models. We are right now in the process of trying to validate some of these dependencies in human samples to try and understand better how faithful these models are to human disease, but they strongly represented a key innovation, as they are uniquely able to recapitulate transformation from indolent CLL, which is something that is uniquely affordable in these platforms, and not so much so in PDX and xenografts that are instead based on transplantation of primary samples into immunodeficient recipients.

We are of course, in the process of further understanding functional dependencies, and therapeutic vulnerabilities, also in the context of checkpoint blockade therapy, which seems to be more effective in Richter’s patients, as opposed to CLL, we still don’t understand why. And we are right now in the process of understanding it through both the modeling, and of course, other efforts in the lab are focused on the human analysis. And we do think that these studies will really allow to highlight key functional pathways that can be then targeted for therapy, and provide models that uniquely allow to study therapeutic options, and to evaluate even the effect of single agents or combinatorial treatments in vivo.

 

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