Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica. 2014 Oct;99(10):e188-92.
Bandapalli O.R., M. Zimmermann, C. Kox, M. Stanulla, M. Schrappe, W.-D. Ludwig, R. Koehler, M.U. Muckenthaler, A.E. Kulozik. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with T-ALL. Haematologica 2013 Jan 24
Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, Te Kronnie G, Cario G, Cazzaniga G, Kulozik AE, Stanulla M, Schrappe M, Biondi A, Basso G, Bercovich D, Muckenthaler MU, Izraeli S. Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. Journal of Experimental Medicine 208:901-918. (2011).
Kox, C, M. Zimmermann, M. Stanulla, M. S. Leible, M. Schrappe, W.-D. Ludwig, M. Muckenthaler, A.E. Kulozik. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL can be separated from NOTCH pathway activation by FBXW7 loss of function.
Leukemia 24:2005-13 (2010).
Kulozik A.E. Taking childhood leukemia personally. Blood 116:4737-8 (2010).
Remke M, S. Pfister, C. Kox, G. Toedt, N. Becker, A. Benner, W. Werft, S. Breit, S. Liu, F. Engel, A. Wittmann, M. Zimmermann, M. Stanulla, M. Schrappe, W.-D. Ludwig, B. Radlwimmer, M.U. Muckenthaler, P. Lichter, A.E. Kulozik. High-resolution genomic profiling of childhood T-ALL reveals frequent copy number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response Blood 114:1053-1062 (2009)
Breit S., M. Stanulla, T. Flohr, M. Schrappe, W.-D. Ludwig, G. Tolle, M. Happich, M. U. Muckenthaler, A. E. Kulozik. Activating NOTCH1 Mutations Predict Favourable Early Treatment Response and Long Term Outcome in Childhood Precursor T-Cell Lymphoblastic Leukemia Blood 108: 1151-1157 (2006).
Kulozik Research Group. Personalized medicine in pediatric oncology
I. Research area: Individualized leukemia therapy
An important prerequisite for the successful treatment of malignant diseases in general and leukemias in particular is the awareness that, in spite of their morphological similarities, these illnesses are very diverse genetically, due to many different patterns of acquired somatic mutations. This diversity means that patients will respond very differently to treatment and that the success of their therapy and their long-term prognosis also vary greatly (Kulozik, Blood 2010).
Our scientific focus lies on an important subgroup of leukemias in children and adolescents, the T-cell acute lymphoblastic leukemias (T-ALL). Overall, the treatment prognosis of this disease is similar to that of the more common B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, T-ALL patients who suffer a relapse despite a well-executed treatment plan have a particularly bad prognosis. That is why, for this type of leukemia in particular, it is essential to determine valid risk factors as early as possible in the treatment. This will allow doctors to determine the patient's individual risk of a recurrence, adjust the intensity of therapy accordingly and thus minimize the danger of a relapse. In addition, modern genetic tests permit us to identify the individual dysregulated pathways in the leukemia cell. These findings can help us determine which medication and drug combinations can be effective against the individual leukemia and which substances have the potential to become new cancer drugs.
We conduct our leukemia research in close cooperation with the BFM network, an association of hospitals in Germany, Austria, Italy and parts of Switzerland that specialize in the treatment of children and adolescents with leukemia. This has enabled us to collect very well documented clinical data and complex molecular biological test results from the largest international group of T-ALL patients. An analysis of the data reveals new and unexpected findings: The TGF-ß pathway, which is important for the normal regulation of immune cells, is frequently inactive in T-ALL patients, while the Pi3K/AKT pathway, which is responsible for stimulating proliferation and regulating growth-stimulating metabolic processes, is often active (Remke et al Blood 2009). This means that an inhibition of the PI3K/AKT pathway specifically in T-ALL patients with PI3K/AKT activation could be a new and viable treatment option. Another interesting fact is that in a subgroup of T-ALL patients the JAK/STAT pathway is stimulated through the activation of the IL7 receptor (Shochat et al. J Exp. Med 2011).
Our analyses also show that children and adolescents with T-ALL and the very frequent activation of the NOTCH pathway have a particularly good chance of recovery even with a low-intensity therapy (Breit et al. Blood 2006, Kox et al. Leukemia 2010). By contrast, patients with an inactive PTEN tumor suppressor, a physiologically important regulator of the PI3K/AKT pathway, are particularly difficult to treat successfully, especially if their leukemia is not characterized by a simultaneous activation of the NOTCH pathway. Initial clinical data indicates, however, that patients from this particular subgroup may benefit from a more intensive therapy (Bandapalli et al. 2013, see below).
We currently use analyses of the complete genome of leukemia cells in order to identify risk factors that might lead to a relapse. Moreover, we want to specify the dysregulated molecular mechanisms that mark the difference between an initial leukemia that responds well to treatment and a recurrent leukemia in the same patient that proves far less sensitive to therapy. We hope that these analyses will enable us to further minimize our patients' individual risk of a recurrence and improve treatment in case a relapse does occur.
and the members of Kulozik group.
III. Project funding
Manfred Lautenschläger Foundation