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CLL loss-of-function lesions distinctly impact B cell developmental and survival trajectories in B-cell restricted mouse models

ABSTRACT: Mouse models represent invaluable tools for the systematic evaluation of cancer drivers, yet those that address the impact of putative genetic drivers of chronic lymphocytic leukemia (CLL) on B cell development and function are largely lacking. To study recurrent loss-of-function (LOF) mutations observed in human CLL, we established a robust transplant model that can rapidly evaluate genetic lesions, based on CRISPR-Cas9–mediated gene knockout restricted to B cells. Using this system, we successfully generated six LOF-expressing models with B cell-specific depletion of Atm, Birc3, Trp53, Chd2, Samhd1 or Mga genes. Transcriptomic analyses identified presence of shared transcriptional networks associated with presence of the 6 modeled LOF mutations, related to increased B cell fitness in vitro and in vivo. We further identified a unique role for Mga in modulating B cell development through dysregulation of MYC and NOTCH signaling targets. None of the individual lesions led to CLL development, after 24 months of observation, supporting the relevance of combinatorial mutations for CLL development in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE197061 | GEO | 2022/12/05

REPOSITORIES: GEO

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Dissection of Richter’s syndrome pathogenesis and treatment through multiplexed CRISPR-based mouse models

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2022-12-05 | GSE186137 | GEO

Genetic dynamics in untreated chronic lymphocytic leukemia patients with either stable or progressive disease: a longitudinal study.

Project description:We investigated at two time points a longitudinal cohort of 27 untreated Chronic Lymphocytic Leukemia (CLL) patients with either stable or progressive disease. The sequenced genes included BCOR, EGR2, HIST1H1E, ITPKB, KRAS, MED12, NRAS, RIPK1, SAMHD1, ATM, BIRC3, BRAF, CHD2, DDX3X, DDX3Y, FBXW7, KIT, KLHL6, MAPK1, MYD88, NOTCH1, PIK3CA, POT1, SF3B1, TP53, XPO1 and ZMYM3, which were previously identified as mutated in CLL studies.

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