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ABT-199 mediated inhibition of BCL2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia

Sofie Peirs UGent, Filip Matthijssens UGent, Steven Goossens, Charles De Bock, Kirsten Canté-Barrett, Tim Lammens UGent, Inge Van de Walle, Barbara De Moerloose UGent, Yves Benoit UGent, Bruce Poppe UGent, et al. (2014) European Hematology Association, 19th Congress, Abstracts.
abstract
Background: T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of ALL with survival rates that gradually improved over the last years mainly through introduction of intensified chemotherapy. However, the clinical outcome of resistant or refractory T-ALL remains extremely poor. Aims: In this study, we investigated whether targeting BCL2 by the specific inhibitor ABT-199 might serve as a new therapeutic strategy in human T-ALL. Methods: Two independent T-ALL patient cohorts as well as independent sets of sorted normal T-cell populations were analyzed by gene expression profiling and/or western blot analysis. IC50 values for ABT-199 were determined in a panel of T-ALL cell lines and in a series of genetically well-characterized primary T-ALL samples. Xenografts of luciferase positive human T-ALLs were used to evaluate the in vivo sensitivity of human T-ALL towards ABT-199 in immunodeficient NSG mice. Results: Gene expression profiling analysis in a large panel of primary T-ALL samples confirmed that high expression of anti-apoptotic BCL2 is a hallmark of immature subtypes of T-ALL. As normal T-cell development serves as the conceptual framework for the understanding of T-ALL biology, we wondered whether high BCL2 expression in immature T-ALL is merely a reflection of the spatiotemporal regulation of BCL2 during T-cell development. Indeed, BCL2 expression is high in CD34+ T cell progenitors and gradually decreases upon differentiation with the lowest values in CD4+ CD8+ double positive T-cells. Interestingly, BCL2L1 expression showed an opposite trend, suggesting an anti-apoptotic switch from BCL2 to Bcl-xL during T-cell maturation. Next, we determined the IC50 values for ABT-199 in a panel of 11 human T-ALL cell lines and observed a strong negative correlation between the IC50 values and BCL2 mRNA (Spearman r = -0.85, p-value = 0.0015) and BCL2 protein (Spearman r = -0.7, p-value = 0.0204) levels. Mature T-ALL cell lines showed modest responses towards ABT-199 treatment with IC50 values ranging from 0.2 to 10µM. However and most notably, the cell line LOUCY, which shows a transcriptional program highly related to early immature T-ALLs, was highly sensitive towards ABT-199 treatment (IC50 = 13.9nM). As expected, induction of apoptosis upon ABT-199 treatment in LOUCY cells was associated with a strong induction of caspase activity. Subsequently, we selected primary T-ALL samples that represent major molecular genetic subtypes of T-ALL in order to determine in vitro ABT-199 sensitivity of immature, TLX1/TLX3, HOXA or TAL1/LMO2 positive T-cell leukemias. Most (5 out of 6) TAL1/LMO2 positive leukemias showed limited response to ABT-199 treatment. In contrast, half of the immature, TLX3 and HOXA positive primary leukemias were highly sensitive to ABT-199 with low IC50 values (< 50nM). Thus, it is clear that ABT-199 sensitivity is not uniform within a particular molecular genetic T-ALL subtype. Therefore, we hypothesize that BCL2 dependency in human T-ALL is initially determined by its cell of origin, but will ultimately be defined by the additional cooperative genetic defects that occur in each T-ALL patient sample. Finally, we performed xenograft experiments using luciferase positive LOUCY cells in which leukemic growth of LOUCY cells was visualized using bioluminescence. Treatment of established xenograft tumors with 100 mg ABT-199/kg for 4 days resulted in a significant reduction of leukemic burden (p-value = 0.0295). Summary/Conclusion: In conclusion, our study highlights BCL2 as an attractive molecular target in specific subtypes of human T-ALL, which could be exploited by the BH3-mimetic drug ABT-199.
Please use this url to cite or link to this publication:
author
organization
year
type
conference
publication status
published
subject
keyword
T cell acute lymphoblastic leukemia, Targeted therapy, BCL2
in
European Hematology Association, 19th Congress, Abstracts
conference name
19th Congress of the European Hematology Association (EHA)
conference location
Milan, Italy
conference start
2014-06-12
conference end
2014-06-15
language
English
UGent publication?
yes
classification
C3
additional info
oral presentation
id
5707585
handle
http://hdl.handle.net/1854/LU-5707585
date created
2014-09-22 19:02:12
date last changed
2016-12-19 15:37:13
@inproceedings{5707585,
  abstract     = {Background: T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of ALL with survival rates that gradually improved over the last years mainly through introduction of intensified chemotherapy. However, the clinical outcome of resistant or refractory T-ALL remains extremely poor.
Aims: In this study, we investigated whether targeting BCL2 by the specific inhibitor ABT-199 might serve as a new therapeutic strategy in human T-ALL.
Methods: Two independent T-ALL patient cohorts as well as independent sets of sorted normal T-cell populations were analyzed by gene expression profiling and/or western blot analysis. IC50 values for ABT-199 were determined in a panel of T-ALL cell lines and in a series of genetically well-characterized primary T-ALL samples. Xenografts of luciferase positive human T-ALLs were used to evaluate the in vivo sensitivity of human T-ALL towards ABT-199 in immunodeficient NSG mice.
Results: Gene expression profiling analysis in a large panel of primary T-ALL samples confirmed that high expression of anti-apoptotic BCL2 is a hallmark of immature subtypes of T-ALL. As normal T-cell development serves as the conceptual framework for the understanding of T-ALL biology, we wondered whether high BCL2 expression in immature T-ALL is merely a reflection of the spatiotemporal regulation of BCL2 during T-cell development. Indeed, BCL2 expression is high in CD34+ T cell progenitors and gradually decreases upon differentiation with the lowest values in CD4+ CD8+ double positive T-cells. Interestingly, BCL2L1 expression showed an opposite trend, suggesting an anti-apoptotic switch from BCL2 to Bcl-xL during T-cell maturation.
Next, we determined the IC50 values for ABT-199 in a panel of 11 human T-ALL cell lines and observed a strong negative correlation between the IC50 values and BCL2 mRNA (Spearman r = -0.85, p-value = 0.0015) and BCL2 protein (Spearman r = -0.7, p-value = 0.0204) levels. Mature T-ALL cell lines showed modest responses towards ABT-199 treatment with IC50 values ranging from 0.2 to 10{\textmu}M. However and most notably, the cell line LOUCY, which shows a transcriptional program highly related to early immature T-ALLs, was highly sensitive towards ABT-199 treatment (IC50 = 13.9nM). As expected, induction of apoptosis upon ABT-199 treatment in LOUCY cells was associated with a strong induction of caspase activity.
Subsequently, we selected primary T-ALL samples that represent major molecular genetic subtypes of T-ALL in order to determine in vitro ABT-199 sensitivity of immature, TLX1/TLX3, HOXA or TAL1/LMO2 positive T-cell leukemias. Most (5 out of 6) TAL1/LMO2 positive leukemias showed limited response to ABT-199 treatment. In contrast, half of the immature, TLX3 and  HOXA positive primary leukemias were highly sensitive to ABT-199 with low IC50 values ({\textlangle} 50nM). Thus, it is clear that ABT-199 sensitivity is not uniform within a particular molecular genetic T-ALL subtype. Therefore, we hypothesize that BCL2 dependency in human T-ALL is initially determined by its cell of origin, but will ultimately be defined by the additional cooperative genetic defects that occur in each T-ALL patient sample.
Finally, we performed xenograft experiments using luciferase positive LOUCY cells in which leukemic growth of LOUCY cells was visualized using bioluminescence. Treatment of established xenograft tumors with 100 mg ABT-199/kg for 4 days resulted in a significant reduction of leukemic burden (p-value = 0.0295).
Summary/Conclusion: In conclusion, our study highlights BCL2 as an attractive molecular target in specific subtypes of human T-ALL, which could be exploited by the BH3-mimetic drug ABT-199.},
  author       = {Peirs, Sofie and Matthijssens, Filip and Goossens, Steven and De Bock, Charles and Cant{\'e}-Barrett, Kirsten and Lammens, Tim and Van de Walle, Inge and De Moerloose, Barbara and Benoit, Yves and Poppe, Bruce and Taghon, Tom and Cools, Jan and Meijerink, Jules and Soulier, Jean and Speleman, Franki and Van Vlierberghe, Pieter},
  booktitle    = {European Hematology Association, 19th Congress, Abstracts},
  keyword      = {T cell acute lymphoblastic leukemia,Targeted therapy,BCL2},
  language     = {eng},
  location     = {Milan, Italy},
  title        = {ABT-199 mediated inhibition of BCL2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia},
  year         = {2014},
}

Chicago
Peirs, Sofie, Filip Matthijssens, Steven Goossens, Charles De Bock, Kirsten Canté-Barrett, Tim Lammens, Inge Van de Walle, et al. 2014. “ABT-199 Mediated Inhibition of BCL2 as a Novel Therapeutic Strategy in T-cell Acute Lymphoblastic Leukemia.” In European Hematology Association, 19th Congress, Abstracts.
APA
Peirs, S., Matthijssens, F., Goossens, S., De Bock, C., Canté-Barrett, K., Lammens, T., Van de Walle, I., et al. (2014). ABT-199 mediated inhibition of BCL2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. European Hematology Association, 19th Congress, Abstracts. Presented at the 19th Congress of the European Hematology Association (EHA).
Vancouver
1.
Peirs S, Matthijssens F, Goossens S, De Bock C, Canté-Barrett K, Lammens T, et al. ABT-199 mediated inhibition of BCL2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. European Hematology Association, 19th Congress, Abstracts. 2014.
MLA
Peirs, Sofie, Filip Matthijssens, Steven Goossens, et al. “ABT-199 Mediated Inhibition of BCL2 as a Novel Therapeutic Strategy in T-cell Acute Lymphoblastic Leukemia.” European Hematology Association, 19th Congress, Abstracts. 2014. Print.