A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion

Abstract

SUMMARY SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remain elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor (BCR) signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.

Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns

“…In CLL, mutations in the HEAT-repeat domain of SF3B1, such as the K700E hotspot mutation, have been shown to associate with poor clinical outcome [1][2][3][4] . B-cell-restricted expression of SF3B1 mutation together with Atm deletion leads to CLL-like disease at low penetrance in a mouse model, confirming a contributory driving role of mutated SF3B1 16 . In addition, mutations in SF3B1 induce aberrant splicing patterns that have been well-characterized using short-read sequencing of the transcriptome.…”

“…This downregulation was corroborated by reanalyzing CLL, Nalm-6 cell line, and TCGA BRCA short-read datasets with mutant SF3B1. CLL has been shown to contain elevated levels of splicing alterations, regardless of SF3B1 mutation status 16,66 . The subset of introns that exhibited increased splicing in the mutant point to a different intron retention landscape in CLL SF3B1 K700E .…”

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

“…First and foremost, comparisons between a male-excessive and a female-excessive cohort must be avoided [37]. Moreover, the generation of additional CLL models should be facilitated [38,39], with consideration to any possible disparity in CLL development between the sexes.…”

CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

“…4c). Interestingly, SF3B1 mutations, which also play a role on the DNA damage response [30,41], showed a trend towards higher sensitivity to the combination as well. On the other hand, TP53, NOTCH1 or XPO1 mutations did not have an influence on the response to the combination of olaparib and ibrutinib (Fig.…”

“…One of the major impediments to the study of CLL biology has been the lack of cellular models faithfully representing the key genetic events of this disease, such as del(11q). While some studies have interrogated the biological impact of diverse individual CLL-associated genetic alterations [25][26][27][28][29], very few have analyzed the effects of concurrently expressed mutations in CLL [30]. Recently, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology has allowed the efficient generation of mutations and chromosomal alterations in human cell lines and animal models, opening new approaches for modeling human diseases [31][32][33][34].…”