Abstract
BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.
Highlights
Chronic lymphocytic leukemia (CLL) patients harboring 11q22.3 deletion (del(11q)) are characterized by the presence of bulky lymphadenopathy, rapid disease progression and short time to first treatment (TTFT) and overall survival (OS) [1,2,3,4], even in early stage Binet A CLL cases [5]
CRISPR/Cas9-mediated generation of isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations In order to understand how monoallelic or biallelic BIRC3 loss contributes to the pathobiology of del(11q) CLL, we used the
Del(11q) is one of the most frequent cytogenetic abnormalities occurring in CLL patients [4, 35, 36], yet, the functional consequences of the haploinsufficiency of the vast majority of genes comprised within this region remains largely unknown
Summary
Chronic lymphocytic leukemia (CLL) patients harboring 11q22.3 deletion (del(11q)) are characterized by the presence of bulky lymphadenopathy, rapid disease progression and short time to first treatment (TTFT) and overall survival (OS) [1,2,3,4], even in early stage Binet A CLL cases [5]. The size of this deletion is heterogeneous, it can cover a region greater than 20 Mb in most of the patients, involving the loss of over a hundred genes [6]. BIRC3 mutations have been found to be enriched in fludarabine relapsed/refractory CLL cases in some cohorts [10, 18], the mechanistic insights by which BIRC3 mutations could contribute to fludarabine resistance have not been elucidated
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