NOTCH1 repression of PKC-θ in T-ALL reduces ROS in LICs and promotes tumor-initiating activity.

  • Major finding: NOTCH1 repression of PKC-θ in T-ALL reduces ROS in LICs and promotes tumor-initiating activity.

  • Mechanism: NOTCH1-induced RUNX3 suppresses RUNX1, which stimulates PKC-θ expression and ROS production.

  • Impact: Modulation of PKC-θ expression or ROS levels may impair LIC activity in patients with T-ALL.

The limited efficacy of chemotherapeutic agents in treating T-cell acute lymphoblastic leukemia (T-ALL) has been attributed to the persistence of leukemia-initiating cells (LIC) that are resistant to apoptosis and drug treatments, underscoring the need to identify mechanisms that regulate the activity and survival of these cells. Giambra and colleagues investigated the role of reactive oxygen species (ROS), which cause oxidative damage particularly in normal hematopoietic stem cells and cancer stem cells, in T-ALL LICs. In transgenic mouse models of T-ALL driven by constitutively activated NOTCH1 or mutant KRAS, as well as in xenograft-expanded human T-ALL samples, cells with increased LIC activity were enriched in the CD44-positive, ROS-low subset of leukemia cells. The low ROS levels in these cells were correlated with reduced expression of protein kinase C-θ (PKC-θ), which controls ROS production in normal T cells, suggesting that this kinase may regulate ROS accumulation, and thus LIC activity, in T-ALL. In support of this idea, PKC-θ-deficient murine T-ALLs exhibited diminished ROS accumulation and enhanced tumor formation, whereas enforced PKC-θ expression in mouse and human leukemias resulted in elevated ROS levels and significantly impaired leukemia initiation. PKC-θ expression was indirectly suppressed by a NOTCH1-initiated transcriptional cascade, in which activated NOTCH1 induced runt-related transcription factor (RUNX) 3, which in turn repressed the expression of RUNX1, a tumor suppressor that activated PKC-θ expression in human T-ALL cells. Consistent with this mechanism, NOTCH blockade using a θ-secretase inhibitor decreased RUNX3 expression, stimulated RUNX1 and PKC-θ expression, and increased ROS accumulation in a PKC-θ-dependent manner. These results identify a crucial link between NOTCH1, which is often mutated in human T-ALL, and PKC-θ in promoting T-ALL and support the development of strategies to augment PKC-θ activity as a means to improve the treatment of patients with T-ALL.

Giambra V, Jenkins CR, Wang H, Lam SH, Shevchuk OO, Nemirovsky O, et al. NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species. Nat Med 2012 Oct 21 [Epub ahead of print].