Fig. 10.

Proposed model of T-PLL development. Top: Projections from an ‘unaffected’ thymic emigrant (left) compared to the scenario of a post-thymic T-PLL precursor (right box) with inappropriate expression of TCL1 and deficient ATM. Effects of this postulated initiating core lesion of TCL1^up/ATM^def on the key signaling branches and functions of ATM are highlighted by differential arrows. It includes perturbation of some of ATM’s safeguarding tasks by TCL1 resulting in cell-death evasion. The ‘TCL1’-lesion refers to the deregulation of any TCL1 family member. TCL1^up/ATM^def jointly confer a functional signature of ATM to be inefficient in counteracting oxidative damage, to maintain telomere and genome integrity, and to activate protective p53 programs. Timeline: Chronology assumptions are based on identified frequencies in sCNA data and tumor fractions in sequencing data. Constitutive TCL1 expression and loss-of-negative regulators (e.g., CTLA4) cause amplifications of TCR-derived survival signals. In the context of dysfunctional ATM this entertains ROS accumulation and genomic instability, which in turn entails further alterations of oncogenes like MYC, of epigenetic modifiers, and of miR processing (e.g., AGO2). Overt-stage autonomous proliferation, including escape from niche-defined homeostatic control relies on independence from milieu input, as potentially conveyed by JAK/STAT mutations. Emerging data, e.g., on the impact of JAK/STAT signaling on non-canonical functions of histone modulators like EZH2⁷⁷ indicate yet unrecognized cross-talks between the affected functional branches