Proposed integrative model of oncogenic TCL1A through the promotion of genomic instability in malignant B-cells. Overexpression of TCL1A causes genomic instability via multiple pathways: (i) deficient repair of DNA damage, (ii) an accelerated cell cycle transition, (iii) susceptibility to aneuploidy (data for i-iii presented in this report), and (iv) apoptosis resistance (published before). Key molecules through which these effects (i.e. via physical interaction with TCL1A) are mediated are highlighted. We show here that overexpression of TCL1A leads to a decreased phosphorylation of ATM and reduced expression of p53 upon genotoxic stress. This might cause impaired sensing and processing of DNA insults (exogeneous or as part of DNA replication), and deficient G2/M checkpoint control, contributing to (i) and (ii). The interaction of TCL1A with molecules from the mitotic checkpoint complex (MCC), including CDC20, might form the basis of the observed accelerated cell cycle transition by deregulating the mitotic checkpoint, contributing to (ii) and (iii). Furthermore, the high frequency of aberrant spindles seen in TCL1A-overexpressing cells promotes the observed aneuploidy. The already well-established role of TCL1A in augmenting AKT phosphorylation6,13,16 leads to increased survival signaling and thereby to apoptotic resistance (perturbation of a safeguarding mechanism). Together, TCL1A overexpression leads to a premature, DNA-damage-prone cell cycle checkpoint transition, which contributes to the TCL1A transforming capability in concert with impaired repair and hyperactive pro-survival signaling.
