Novel Richter's syndrome xenograft models to study genetic architecture, biology and therapy responses

Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed over-activation of the B cell receptor, NF-kB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of RS represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.

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