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. 2010 Dec;24(12):2005-13.
doi: 10.1038/leu.2010.203. Epub 2010 Oct 14.

The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function

C Kox  1 , M Zimmermann, M Stanulla, S Leible, M Schrappe, W-D Ludwig, R Koehler, G Tolle, O R Bandapalli, S Breit, M U Muckenthaler, A E Kulozik
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Free PMC article

The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function

C Kox et al. Leukemia. 2010 Dec.
Free PMC article

Abstract

Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains an important challenge in pediatric oncology. Because of the particularly poor prognosis of relapses, it is vital to identify molecular risk factors allowing early and effective treatment stratification. Activating NOTCH1 mutations signify a favorable prognosis in patients treated on ALL-BFM protocols. We have now tested if NOTCH pathway activation at different steps has similar clinical effects and if multiple mutations in this pathway function synergistically. Analysis of a validation set of 151 T-ALL patients and of the total cohort of 301 patients confirms the low relapse rate generally and the overall favorable effect of activating NOTCH1 mutations. Subgroup analysis shows that the NOTCH1 effect in ALL-BFM is restricted to patients with rapid early treatment response. Inactivation of the ubiquitin ligase FBXW7 is associated with rapid early treatment response and synergizes with NOTCH1 receptor activation. However, the effect of FBXW7 inactivation is separable from NOTCH1 activation by not synergizing with NOTCH1 mutations in predicting favorable long-term outcome, which can probably be explained by the interaction of FBXW7 with other clients. Finally, the comparison with other European protocols suggests that the NOTCH effect is treatment dependent generally and may depend on the intensity of central nervous system-directed therapy specifically.

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Figures

Figure 1
Figure 1
Activating NOTCH1 mutations predict an excellent long-term outcome in T-ALL. (a) Kaplan–Meier estimate of the pEFS in NOTCH1-mutated and NOTCH1-non-mutated patients from the total cohort (n=301). (b) pCIR in NOTCH1-mutated and NOTCH1-non-mutated patients from the total cohort (n=301). (c) Kaplan–Meier estimate of the pEFS in NOTCH1-mutated and NOTCH1-non-mutated patients from the validation set (n=151). (d) pCIR in NOTCH1-mutated and NOTCH1-non-mutated patients from the validation set (n=151). The 18 events in the NOTCH1-non-mutated group were 14 relapses, 3 deaths in continuous complete remission and 1 death before complete remission. The 10 events in the NOTCH1-mutated group were 5 relapses, 4 deaths in continuous complete remission and 1 death before complete remission.
Figure 2
Figure 2
The favorable effect of activating NOTCH1 mutations on long-term outcome is restricted to the SR/MR group. (a) Kaplan–Meier estimate of the probability of pEFS in NOTCH1-mutated and NOTCH1-non-mutated SR/MR patients. (b) pCIR in NOTCH1-mutated and NOTCH1-non-mutated SR/MR patients. (c) Kaplan–Meier estimate of the pEFS in NOTCH1-mutated and NOTCH1-non-mutated HR patients. (d) pCIR in NOTCH1-mutated and NOTCH1-non-mutated HR patients.
Figure 3
Figure 3
Inactivating FBXW7 mutations do not predict better long-term outcome in T-ALL. (a) Kaplan–Meier estimate of the pEFS in FBXW7-mutated and FBXW7-non-mutated patients. (b) pCIR in FBXW7-mutated and FBXW7-non-mutated patients.
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