THE NUP214-ABL1 FUSION COOPERATES WITH TLX1 IN THE DEVELOPMENT OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Vanden Bempt M. 06/10/16; 133143; P155
Ms. Marlies Vanden Bempt
Contributions
Contributions
Abstract
Abstract: P155
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The episomal NUP214-ABL1 fusion is observed in 6% of T-ALL patients. The resulting NUP214-ABL1 fusion protein is a constitutively activated tyrosine kinase, which activates STAT5 and ERK signalling, thereby stimulating proliferation and survival. Significantly, almost all T-ALL cases with the NUP214-ABL1 fusion also harbour chromosomal translocations resulting in the overexpression of the homeobox transcription factors TLX1 or TLX3.
Aims
To determine whether (i) co-expression of NUP214-ABL1 fusion and TLX1 cooperate together in leukemia development; and (ii) to understand the molecular mechanisms underlying any cooperation at the transcriptional level.
Methods
We have generated a conditional loxP-STOP-loxP NUP214-ABL1 knock-in mouse model, in which NUP214-ABL1 expression can be activated by Cre. We crossed these mice with Tg(CD4-Cre) mice, in which Cre is expressed in developing T-cells, and then subsequently with Tg(Lck-TLX1) mice, expressing TLX1 under control of the T-cell specific Lck promoter. These crossings resulted in a Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model. Using RNA-sequencing and ChIP-sequencing, we determined gene expression profiles and binding patterns of STAT5 and TLX1.
Results
The Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model developed a transplantable CD4+/CD8+ T-ALL with a significantly shorter latency (median survival of 193 days) compared to the Tg(Lck-TLX1) mouse model (median survival 385 days) or the Tg(CD4-Cre, NUP214-ABL1) mouse model (no disease), indicating true cooperation between NUP214-ABL1 and TLX1 during T-ALL development. Gene expression profiling revealed that there is significant upregulation of the JAK-STAT pathway, the mTOR signalling pathway and the Notch1 signaling pathway in the Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model, compared to the Tg(Lck-TLX1) mouse model. The cooperation between NUP214-ABL1 and TLX1 was also investigated in a human context using the T-ALL cell line ALL-SIL, which carries these two oncogenic alterations. ChIP sequencing results showed that STAT5 and TLX1 have overlapping binding patterns on genes that have been identified as STAT5 target genes. We are currently validating these results in our transgenic mouse model.
Conclusion
The NUP214-ABL1 fusion and TLX1 overexpression cooperate to drive T-ALL development.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Fusion, Signaling, Transcription factor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The episomal NUP214-ABL1 fusion is observed in 6% of T-ALL patients. The resulting NUP214-ABL1 fusion protein is a constitutively activated tyrosine kinase, which activates STAT5 and ERK signalling, thereby stimulating proliferation and survival. Significantly, almost all T-ALL cases with the NUP214-ABL1 fusion also harbour chromosomal translocations resulting in the overexpression of the homeobox transcription factors TLX1 or TLX3.
Aims
To determine whether (i) co-expression of NUP214-ABL1 fusion and TLX1 cooperate together in leukemia development; and (ii) to understand the molecular mechanisms underlying any cooperation at the transcriptional level.
Methods
We have generated a conditional loxP-STOP-loxP NUP214-ABL1 knock-in mouse model, in which NUP214-ABL1 expression can be activated by Cre. We crossed these mice with Tg(CD4-Cre) mice, in which Cre is expressed in developing T-cells, and then subsequently with Tg(Lck-TLX1) mice, expressing TLX1 under control of the T-cell specific Lck promoter. These crossings resulted in a Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model. Using RNA-sequencing and ChIP-sequencing, we determined gene expression profiles and binding patterns of STAT5 and TLX1.
Results
The Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model developed a transplantable CD4+/CD8+ T-ALL with a significantly shorter latency (median survival of 193 days) compared to the Tg(Lck-TLX1) mouse model (median survival 385 days) or the Tg(CD4-Cre, NUP214-ABL1) mouse model (no disease), indicating true cooperation between NUP214-ABL1 and TLX1 during T-ALL development. Gene expression profiling revealed that there is significant upregulation of the JAK-STAT pathway, the mTOR signalling pathway and the Notch1 signaling pathway in the Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model, compared to the Tg(Lck-TLX1) mouse model. The cooperation between NUP214-ABL1 and TLX1 was also investigated in a human context using the T-ALL cell line ALL-SIL, which carries these two oncogenic alterations. ChIP sequencing results showed that STAT5 and TLX1 have overlapping binding patterns on genes that have been identified as STAT5 target genes. We are currently validating these results in our transgenic mouse model.
Conclusion
The NUP214-ABL1 fusion and TLX1 overexpression cooperate to drive T-ALL development.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Fusion, Signaling, Transcription factor
Abstract: P155
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The episomal NUP214-ABL1 fusion is observed in 6% of T-ALL patients. The resulting NUP214-ABL1 fusion protein is a constitutively activated tyrosine kinase, which activates STAT5 and ERK signalling, thereby stimulating proliferation and survival. Significantly, almost all T-ALL cases with the NUP214-ABL1 fusion also harbour chromosomal translocations resulting in the overexpression of the homeobox transcription factors TLX1 or TLX3.
Aims
To determine whether (i) co-expression of NUP214-ABL1 fusion and TLX1 cooperate together in leukemia development; and (ii) to understand the molecular mechanisms underlying any cooperation at the transcriptional level.
Methods
We have generated a conditional loxP-STOP-loxP NUP214-ABL1 knock-in mouse model, in which NUP214-ABL1 expression can be activated by Cre. We crossed these mice with Tg(CD4-Cre) mice, in which Cre is expressed in developing T-cells, and then subsequently with Tg(Lck-TLX1) mice, expressing TLX1 under control of the T-cell specific Lck promoter. These crossings resulted in a Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model. Using RNA-sequencing and ChIP-sequencing, we determined gene expression profiles and binding patterns of STAT5 and TLX1.
Results
The Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model developed a transplantable CD4+/CD8+ T-ALL with a significantly shorter latency (median survival of 193 days) compared to the Tg(Lck-TLX1) mouse model (median survival 385 days) or the Tg(CD4-Cre, NUP214-ABL1) mouse model (no disease), indicating true cooperation between NUP214-ABL1 and TLX1 during T-ALL development. Gene expression profiling revealed that there is significant upregulation of the JAK-STAT pathway, the mTOR signalling pathway and the Notch1 signaling pathway in the Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model, compared to the Tg(Lck-TLX1) mouse model. The cooperation between NUP214-ABL1 and TLX1 was also investigated in a human context using the T-ALL cell line ALL-SIL, which carries these two oncogenic alterations. ChIP sequencing results showed that STAT5 and TLX1 have overlapping binding patterns on genes that have been identified as STAT5 target genes. We are currently validating these results in our transgenic mouse model.
Conclusion
The NUP214-ABL1 fusion and TLX1 overexpression cooperate to drive T-ALL development.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Fusion, Signaling, Transcription factor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The episomal NUP214-ABL1 fusion is observed in 6% of T-ALL patients. The resulting NUP214-ABL1 fusion protein is a constitutively activated tyrosine kinase, which activates STAT5 and ERK signalling, thereby stimulating proliferation and survival. Significantly, almost all T-ALL cases with the NUP214-ABL1 fusion also harbour chromosomal translocations resulting in the overexpression of the homeobox transcription factors TLX1 or TLX3.
Aims
To determine whether (i) co-expression of NUP214-ABL1 fusion and TLX1 cooperate together in leukemia development; and (ii) to understand the molecular mechanisms underlying any cooperation at the transcriptional level.
Methods
We have generated a conditional loxP-STOP-loxP NUP214-ABL1 knock-in mouse model, in which NUP214-ABL1 expression can be activated by Cre. We crossed these mice with Tg(CD4-Cre) mice, in which Cre is expressed in developing T-cells, and then subsequently with Tg(Lck-TLX1) mice, expressing TLX1 under control of the T-cell specific Lck promoter. These crossings resulted in a Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model. Using RNA-sequencing and ChIP-sequencing, we determined gene expression profiles and binding patterns of STAT5 and TLX1.
Results
The Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model developed a transplantable CD4+/CD8+ T-ALL with a significantly shorter latency (median survival of 193 days) compared to the Tg(Lck-TLX1) mouse model (median survival 385 days) or the Tg(CD4-Cre, NUP214-ABL1) mouse model (no disease), indicating true cooperation between NUP214-ABL1 and TLX1 during T-ALL development. Gene expression profiling revealed that there is significant upregulation of the JAK-STAT pathway, the mTOR signalling pathway and the Notch1 signaling pathway in the Tg(CD4-Cre, NUP214-ABL1, Lck-TLX1) mouse model, compared to the Tg(Lck-TLX1) mouse model. The cooperation between NUP214-ABL1 and TLX1 was also investigated in a human context using the T-ALL cell line ALL-SIL, which carries these two oncogenic alterations. ChIP sequencing results showed that STAT5 and TLX1 have overlapping binding patterns on genes that have been identified as STAT5 target genes. We are currently validating these results in our transgenic mouse model.
Conclusion
The NUP214-ABL1 fusion and TLX1 overexpression cooperate to drive T-ALL development.
Session topic: Acute lymphoblastic leukemia - Biology 1
Keyword(s): Acute lymphoblastic leukemia, Fusion, Signaling, Transcription factor
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