Thus, to advance further in the genetic manipulation of primary malignant B cell, such as CLL and MCL, we took advantage of our cell culture system that allows the in vitro expansion of patient-derived CLL/MCL cells for several weeks, regardless of the clinico-biological subtype of the disease.10 Using this cell culture system, in which primary cells are exposed to human CD40-ligand, IL21, and BAFF secreted by murine stromal cells, we have now established a robust method for CRISPR-Cas9 editing of patient-derived malignant-activated CLL/MCL cells. The gene discussed is CD40LG; the disease is B-cell chronic lymphocytic leukemia.