Understanding CLL biology through mouse models of human genetics

Abstract

Rapid advances in large-scale next-generation sequencing studies of human samples have progressively defined the highly heterogeneous genetic landscape of chronic lymphocytic leukemia (CLL). At the same time, the numerous challenges posed by the difficulties in rapid manipulation of primary B cells and the paucity of CLL cell lines have limited the ability to interrogate the function of the discovered putative disease "drivers," defined in human sequencing studies through statistical inference. Mouse models represent a powerful tool to study mechanisms of normal and malignant B-cell biology and for preclinical testing of novel therapeutics. Advances in genetic engineering technologies, including the introduction of conditional knockin/knockout strategies, have opened new opportunities to model genetic lesions in a B-cell-restricted context. These new studies build on the experience of generating the MDR mice, the first example of a genetically faithful CLL model, which recapitulates the most common genomic aberration of human CLL: del(13q). In this review, we describe the application of mouse models to the studies of CLL pathogenesis and disease transformation from an indolent to a high-grade malignancy (ie, Richter syndrome [RS]) and treatment, with a focus on newly developed genetically inspired mouse lines modeling recurrent CLL genetic events. We discuss how these novel mouse models, analyzed using new genomic technologies, allow the dissection of mechanisms of disease evolution and response to therapy with greater depth than previously possible and provide important insight into human CLL and RS pathogenesis and therapeutic vulnerabilities. These models thereby provide valuable platforms for functional genomic analyses and treatment studies.

Graphical abstract

Figure 1.

Timeline of human vs murine studies highlighting landmark papers and ASH abstracts related to genetic/epigenetic analyses of human CLL and RS and to the generation of genetically engineered mouse models and xenografts.

Figure 2.

Schematic representation of the integration of human genomic analyses into the generation of mouse models recapitulating human disease drivers. Novel models can be exploited for studies of disease pathogenesis and treatment and allow findings to be translated back into personalized treatment interventions for patients with selected genetic makeups.

Figure 3.

Comutation plot highlighting disease drivers identified in our latest published dataset of 538 CLLs that were since then modeled in mice. Modeled human gene mutations, name of mouse model, and reference study are indicated in the table. Published dataset of 538 CLLs from Landau et al.

Figure 4.

B-cell–restricted strains carrying CLL putative disease drivers and functional interrogation of the role of selected gene mutations in CLL pathogenesis.

Figure 5.

Comparative characteristics of CLL and RS genetically engineered mouse models (GEMMs) and xenografts and their amenability for studies of CLL pathogenesis and treatment.