HEDGEHOG PATHWAY ACTIVATION IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA PREDICTS RESPONSE TO SMO AND GLI1 INHIBITORS
(Abstract release date: 05/19/16)
EHA Library. De Bie J. 06/10/16; 133140; P152
Ms. Jolien De Bie
Contributions
Contributions
Abstract
Abstract: P152
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The hedgehog signaling pathway contributes to embryonic pattern formation and adult tissue homeostasis as it is important to regulate cell proliferation, survival and differentiation. Aberrant activation of the hedgehog pathway through overexpression of the ligands (SHH, IHH) or mutations in signaling components (PTCH1, SMO, SUFU, GLI1) has been described in various solid tumors. The Hedgehog pathway is important for normal T-cell development, but its potential role in the development of T-cell acute lymphoblastic leukemia (T-ALL) is poorly characterized.
Aims
Our aim was to investigate the role of the hedgehog pathway as an oncogenic factor and a potential target for therapy in T-ALL.
Methods
We analyzed gene expression profiles of human T-ALL samples from two independent cohorts. We determined the effects of hedgehog ligand stimulation, downregulation of critical signaling components or pharmacological inhibition of the pathway in T-ALL cell lines, a mouse T-ALL model and in patient derived xenografts.
Results
Gene expression data analysis of primary T-ALL samples revealed that about 25% of T-ALL cases show ectopic expression of the ligands of the hedgehog pathway. A strong correlation between the ligands SHH and IHH with the main transcriptional factors GLI1 and GLI2 and known GLI target genes was observed, indicative of hedgehog pathway activation through an autocrine loop. Pharmacological inhibition of the hedgehog pathway, or siRNA mediated knock-down of key signaling components caused a decrease of proliferation of a subset of T-ALL cell lines, and sensitized the T-ALL cell lines to chemotherapy. In our JAK3-dependent T-ALL mouse model expression of Shh or Ihh provided a growth advantage to the JAK3(M511I) leukemia cells. Finally, we tested if hedgehog pathway inhibition could inhibit the growth of primary T-ALL cells. For this reason patient derived T-ALL xenograft samples were treated with two hedgehog inhibitors ex vivo and in vivo. T-ALL samples with high GLI1 expression were sensitive in both ex vivo and in vivo experimental set up, while T-ALL samples with low or no GLI1 expression were insensitive.
Conclusion
We demonstrate that the hedgehog pathway is activated in a subset of T-ALL patients and that hedgehog pathway activation affects T-ALL cell proliferation and provides partial protection against chemotherapy. Data from patient derived xenograft T-ALL samples confirms that high GLI1 expression predicts sensitivity of T-ALL samples to hedgehog pathway inhibitors.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Leukemia, Mouse model, Oncogene, Signaling
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The hedgehog signaling pathway contributes to embryonic pattern formation and adult tissue homeostasis as it is important to regulate cell proliferation, survival and differentiation. Aberrant activation of the hedgehog pathway through overexpression of the ligands (SHH, IHH) or mutations in signaling components (PTCH1, SMO, SUFU, GLI1) has been described in various solid tumors. The Hedgehog pathway is important for normal T-cell development, but its potential role in the development of T-cell acute lymphoblastic leukemia (T-ALL) is poorly characterized.
Aims
Our aim was to investigate the role of the hedgehog pathway as an oncogenic factor and a potential target for therapy in T-ALL.
Methods
We analyzed gene expression profiles of human T-ALL samples from two independent cohorts. We determined the effects of hedgehog ligand stimulation, downregulation of critical signaling components or pharmacological inhibition of the pathway in T-ALL cell lines, a mouse T-ALL model and in patient derived xenografts.
Results
Gene expression data analysis of primary T-ALL samples revealed that about 25% of T-ALL cases show ectopic expression of the ligands of the hedgehog pathway. A strong correlation between the ligands SHH and IHH with the main transcriptional factors GLI1 and GLI2 and known GLI target genes was observed, indicative of hedgehog pathway activation through an autocrine loop. Pharmacological inhibition of the hedgehog pathway, or siRNA mediated knock-down of key signaling components caused a decrease of proliferation of a subset of T-ALL cell lines, and sensitized the T-ALL cell lines to chemotherapy. In our JAK3-dependent T-ALL mouse model expression of Shh or Ihh provided a growth advantage to the JAK3(M511I) leukemia cells. Finally, we tested if hedgehog pathway inhibition could inhibit the growth of primary T-ALL cells. For this reason patient derived T-ALL xenograft samples were treated with two hedgehog inhibitors ex vivo and in vivo. T-ALL samples with high GLI1 expression were sensitive in both ex vivo and in vivo experimental set up, while T-ALL samples with low or no GLI1 expression were insensitive.
Conclusion
We demonstrate that the hedgehog pathway is activated in a subset of T-ALL patients and that hedgehog pathway activation affects T-ALL cell proliferation and provides partial protection against chemotherapy. Data from patient derived xenograft T-ALL samples confirms that high GLI1 expression predicts sensitivity of T-ALL samples to hedgehog pathway inhibitors.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Leukemia, Mouse model, Oncogene, Signaling
Abstract: P152
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The hedgehog signaling pathway contributes to embryonic pattern formation and adult tissue homeostasis as it is important to regulate cell proliferation, survival and differentiation. Aberrant activation of the hedgehog pathway through overexpression of the ligands (SHH, IHH) or mutations in signaling components (PTCH1, SMO, SUFU, GLI1) has been described in various solid tumors. The Hedgehog pathway is important for normal T-cell development, but its potential role in the development of T-cell acute lymphoblastic leukemia (T-ALL) is poorly characterized.
Aims
Our aim was to investigate the role of the hedgehog pathway as an oncogenic factor and a potential target for therapy in T-ALL.
Methods
We analyzed gene expression profiles of human T-ALL samples from two independent cohorts. We determined the effects of hedgehog ligand stimulation, downregulation of critical signaling components or pharmacological inhibition of the pathway in T-ALL cell lines, a mouse T-ALL model and in patient derived xenografts.
Results
Gene expression data analysis of primary T-ALL samples revealed that about 25% of T-ALL cases show ectopic expression of the ligands of the hedgehog pathway. A strong correlation between the ligands SHH and IHH with the main transcriptional factors GLI1 and GLI2 and known GLI target genes was observed, indicative of hedgehog pathway activation through an autocrine loop. Pharmacological inhibition of the hedgehog pathway, or siRNA mediated knock-down of key signaling components caused a decrease of proliferation of a subset of T-ALL cell lines, and sensitized the T-ALL cell lines to chemotherapy. In our JAK3-dependent T-ALL mouse model expression of Shh or Ihh provided a growth advantage to the JAK3(M511I) leukemia cells. Finally, we tested if hedgehog pathway inhibition could inhibit the growth of primary T-ALL cells. For this reason patient derived T-ALL xenograft samples were treated with two hedgehog inhibitors ex vivo and in vivo. T-ALL samples with high GLI1 expression were sensitive in both ex vivo and in vivo experimental set up, while T-ALL samples with low or no GLI1 expression were insensitive.
Conclusion
We demonstrate that the hedgehog pathway is activated in a subset of T-ALL patients and that hedgehog pathway activation affects T-ALL cell proliferation and provides partial protection against chemotherapy. Data from patient derived xenograft T-ALL samples confirms that high GLI1 expression predicts sensitivity of T-ALL samples to hedgehog pathway inhibitors.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Leukemia, Mouse model, Oncogene, Signaling
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The hedgehog signaling pathway contributes to embryonic pattern formation and adult tissue homeostasis as it is important to regulate cell proliferation, survival and differentiation. Aberrant activation of the hedgehog pathway through overexpression of the ligands (SHH, IHH) or mutations in signaling components (PTCH1, SMO, SUFU, GLI1) has been described in various solid tumors. The Hedgehog pathway is important for normal T-cell development, but its potential role in the development of T-cell acute lymphoblastic leukemia (T-ALL) is poorly characterized.
Aims
Our aim was to investigate the role of the hedgehog pathway as an oncogenic factor and a potential target for therapy in T-ALL.
Methods
We analyzed gene expression profiles of human T-ALL samples from two independent cohorts. We determined the effects of hedgehog ligand stimulation, downregulation of critical signaling components or pharmacological inhibition of the pathway in T-ALL cell lines, a mouse T-ALL model and in patient derived xenografts.
Results
Gene expression data analysis of primary T-ALL samples revealed that about 25% of T-ALL cases show ectopic expression of the ligands of the hedgehog pathway. A strong correlation between the ligands SHH and IHH with the main transcriptional factors GLI1 and GLI2 and known GLI target genes was observed, indicative of hedgehog pathway activation through an autocrine loop. Pharmacological inhibition of the hedgehog pathway, or siRNA mediated knock-down of key signaling components caused a decrease of proliferation of a subset of T-ALL cell lines, and sensitized the T-ALL cell lines to chemotherapy. In our JAK3-dependent T-ALL mouse model expression of Shh or Ihh provided a growth advantage to the JAK3(M511I) leukemia cells. Finally, we tested if hedgehog pathway inhibition could inhibit the growth of primary T-ALL cells. For this reason patient derived T-ALL xenograft samples were treated with two hedgehog inhibitors ex vivo and in vivo. T-ALL samples with high GLI1 expression were sensitive in both ex vivo and in vivo experimental set up, while T-ALL samples with low or no GLI1 expression were insensitive.
Conclusion
We demonstrate that the hedgehog pathway is activated in a subset of T-ALL patients and that hedgehog pathway activation affects T-ALL cell proliferation and provides partial protection against chemotherapy. Data from patient derived xenograft T-ALL samples confirms that high GLI1 expression predicts sensitivity of T-ALL samples to hedgehog pathway inhibitors.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Leukemia, Mouse model, Oncogene, Signaling
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