CLL Disease Severity Is Enhanced in Tcl1 Mice Deficient for Pro-Apoptotic Regulator Noxa

Despite the development of new treatment strategies, chronic lymphocytic leukemia (CLL) remains an incurable disease. Apoptosis dysregulation caused by environmental signaling, predominantly within lymph nodes, plays a key role in CLL maintenance and treatment resistance. In earlier work, we demonstrated that expression of the pro-apoptotic Bcl-2 family member Noxa is increased in circulating CLL cells compared to normal B-cells (1). Moreover, Noxa levels are decreased in CLL cells that reside in the lymph node while its key anti-apoptotic binding partner, Mcl-1, shows a reverse trend (2). This suggests that the decreased  Noxa/MCL-1 ratio within the microenvironment may contribute to enhanced CLL survival. Here we aimed at elucidating a functional role for Noxa in CLL in the context of a murine model by crossing Noxa deficient mice (Noxa-KO) with Eμ.Tcl1-Tg mice (TCL1) mice.

We first established that also in Tcl1 mice the Noxa/Mcl-1 ratio was increased PB vs. LN cells. The phenotype and distribution of leukemic cells was similar in Tcl1 and Noxa-KO/tcl1 mice. Interestingly, the accumulation of CLL cells in the peripheral blood was accelerated in Noxa-KO/TCL1 mice. This was accompanied by a reduction of apoptotic cells in the spleen of Noxa-KO/TCL1 mice. In accordance with these findings, survival of Noxa-KO/Tcl1 mice was decreased compared to the Tcl1 mice (342 days vs. 396 days, p<0.001, Figure 1). Our data suggest a role for Noxa in CLL as a tumor suppressor, and provides a rationale for the use of compounds which may alter the Noxa/Mcl1 balance in patients.

Figure 1. Survival analysis of Noxa-KO/TCL1 mice and TCL1 mice. The Kaplan-Meier curves were  analyzed by a Log-Rank test.

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1.         W. J. Mackus et al., Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia 19, 427-434 (2005).

2.         L. A. Smit et al., Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood 109, 1660-1668 (2007).