A model of genetic evolution of FL. A normal B-cell undergoes immunoglobulin recombination, followed by acquisition of the t(14;18)(q32;q21) founder IGH-BCL2 translocation yielding a premalignant tumor cell precursor, detectable in the majority of older adults in the absence of tumors.16 This precursor acquires 1 or more driver mutations, such as in CREBBP, yielding an early malignant clone. Accelerator mutations are then acquired, such as those in MLL2 and/or TNFRSF14, resulting in a progressed malignant clone with a selective advantage that yields clinical disease. Relapses may originate from either an early malignant clone as in patient LPJ128 (Figure 5), and therefore possess only founder and driver mutations, or from a progressed malignant clone as in patient LPJ041 (Figure 4), and therefore possess a full repertoire of founder, driver and accelerator mutations.
