@article{Obul R. Bandapalli_Martin Zimmermann_Corinne Kox_Martin Stanulla_Martin Schrappe_Wolf-Dieter Ludwig_Rolf Koehler_Martina U. Muckenthaler_Andreas E. Kulozik_2013, place={Pavia, Italy}, title={NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia}, volume={98}, url={https://haematologica.org/article/view/6695}, DOI={10.3324/haematol.2012.073585}, abstractNote={Despite improvements in treatment results for pediatric T-cell acute lymphoblastic leukemia, approximately 20% of patients relapse with dismal prognosis. <em>PTEN</em> inactivation and <em>NOTCH1</em> activation are known frequent leukemogenic events but their effect on outcome is still controversial. We analyzed the effect of <em>PTEN</em> inactivation and its interaction with <em>NOTCH1</em> activation on treatment response and long-term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. We identified <em>PTEN</em> mutations in 52 of 301 (17.3%) of patients. In univariate analyses this was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating <em>PTEN</em> and activating <em>NOTCH1</em> mutations showed marked sensitivity to induction treatment and excellent long-term outcome, which was similar to patients with <em>NOTCH1</em> mutations only, and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone- and minimal residual disease (MRD)-response based medium risk profile, <em>PTEN</em>-mutations without co-existing <em>NOTCH1</em>-mutations represented an MRD-independent highly significant high-risk biomarker. Mutations of <em>PTEN</em> highly significantly indicate a poor prognosis in T-ALL patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by <em>NOTCH1</em> mutations. Although these results have not yet been explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of <em>NOTCH1</em> inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general, and in those with a combination of <em>PTEN</em> and <em>NOTCH1</em&gt; mutations in particular.}, number={6}, journal={Haematologica}, author={Obul R. Bandapalli and Martin Zimmermann and Corinne Kox and Martin Stanulla and Martin Schrappe and Wolf-Dieter Ludwig and Rolf Koehler and Martina U. Muckenthaler and Andreas E. Kulozik}, year={2013}, month={May}, pages={928-936} }