Scientific programme

P26  Poster Session - May 4 - May 6
SOMATIC MUTATIONS

04-May-2017 08:00 17:00
 
 
Abstract: 185
BCL-2 INHIBITION BY ABT-199 POTENTLY INDUCES CELL DEATH IN MDS PROGENITORS DESPITE HIGH-RISK MUTATIONS IN ASXL1, RUNX1, TP53 OR EZH2

A clinical key feature of Myelodysplastic Syndromes (MDS) is variable outcome. Recent findings emphasize the prognostic impact of specific somatic mutations within the MDS clone. Especially alterations in ASXL1, RUNX1, TP53 or EZH2 are associated with a significantly shorten overall survival despite well-established therapeutic approaches. 
The induction of clinical remission in higher-risk MDS critically depends on the capacity of MDS progenitor cells for sustained pro-survival signals. BCL-2 provides protection against various pro-apoptotic stresses. Pharmacologic inhibition of BCL-2 therefore serves as a potent cell death-inducing strategy in MDS. Specifically higher-risk MDS patients present with de-regulated expression of proteins from the BCL-2 family effectively blocking cell death induction at the mitochondria. Our previous work has shown that ABT-199 has a positive therapeutic index in higher-risk MDS when compared to healthy age-matched progenitor cell survival. 
Murine models demonstrate an interaction between ASXL1, RUNX1, EZH2 and BCL-2. We therefore tested the susceptibility of patients bearing a mutational adverse profile to ABT-199. Analyzing BCL-2 gene expression in a large cohort of MDS patients (n=106) and healthy controls (n=110) we did not detect any differences in dependence on the mutational status. These findings were confirmed by immunohistochemistry for BCL-2 in an independent set of bone marrow biopsies of MDS/sAML patients. Our results are in contrast to previous data from murine Asxl1−/− Linc-Kit+ cells where loss of ASXL1 led to a significant downregulation of Bcl-2. Thus, highlighting the impact of primary human samples in MDS. 
Based on these data we tested the therapeutic efficacy of ABT-199 in a number of primary BM samples of MDS/sAML patients presenting with one or two of the indicated mutations in vitro. Controls consisted of MDS/sAML patients bearing no mutation and additionally age-matched healthy controls. Within the high-risk MDS/sAML cohort induction of apoptosis by ABT-199 was similarly effective in mutated and non-mutated samples. Even the accumulation of more than one adverse mutation did not impair the broad apoptotic effect of ABT-199. Healthy controls, low- or intermediate-risk samples were only slightly affected. Treatment response clearly correlated with  BCL-2 expression as measured by intracellular flow cytometry. Also colony forming capacity was reduced by ABT-199 treatment in high-risk MDS/sAML irrespective of the mutational status.
In summary our data demonstrate that ABT-199 effectively induces apoptosis in the stem/progenitor cells of high-risk MDS/sAML samples despite the presence of adverse genetic aberrations offering promising therapeutic options.

 
Co-authors
S. Jilg 1, V. Reidel 1, J. Kauschinger 1, C. Müller-Thomas 1, R. Hauch 1, J. Schauwecker 2, S. Burkhard 3, U. Höckendorf 1, C. Peschel 1, W. Kern 4, T. Haferlach 4, J. Slotta-Huspenina 5, K.S. Götze 5, P.J. Jost 1
1TU Muenchen - Klinikum rechts der Isar, III. Medizinische Klinik, München, Germany
2TU Muenchen - Klinikum rechts der Isar, Klinik für Orthopädie und Sportorthopädie, München, Germany
3Gemeinschaftspraxis Hämato-Onkologie, Pasing, München, Germany
4Munich Leukemia Laboratory, MLL, Munich, Germany
5TU Muenchen - Klinikum rechts der Isar, Institut für Pathologie, München, Germany