VENTX INDUCES EXPANSION OF PRIMITIVE ERYTHROID CELLS AND CONTRIBUTES TO THE DEVELOPMENT OF ACUTE MYELOID LEUKEMIA IN MICE
(Abstract release date: 05/19/16)
EHA Library. Gentner E. 06/10/16; 133162; P174
Mrs. Eva Gentner
Contributions
Contributions
Abstract
Abstract: P174
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Homeobox genes are key factors in the development of acute leukemias. So far, little is known about the role of non-clustered homeobox genes such as VENTX. The Vent-like homeobox gene VENTX is a member of the Vent gene family in mammals and is the mammalian homolog of the Xenopus xvent gene. Our group has previously shown that the homeobox gene VENTX shows high and aberrant expression in human acute myeloid leukemia (AML) characterized by the AML1-ETO (AE) fusion (Rawat et al., PNAS 2010).
Aims
With this study, we wanted to test the functional relevance of VENTX in the development of AE positive AML in mice.
Methods
To address this, mice were transplanted with bone marrow progenitor cells retrovirally engineered to express VENTX or AML1-ETO alone or in combination.
Results
Whereas none of the AML1-ETO mice developed any disease, all the recipients of AML1-ETO/VENTX double transduced cells succumbed to AML after a median latency of 334 days (range 19-403 days) post transplantation. Of note, induced AML cases were positive for erythroid markers such as CD71 and Ter119. Strikingly, VENTX alone induced a massive expansion of the primitive erythroid compartment in all transplanted mice. Furthermore, this massive perturbation in differentiation converted into an acute erythroleukemia in a fraction of mice. All leukemias in the AE/VENTX and the VENTX experimental arms were rapidly transplantable with a median latency of 40 days until leukemia induced death, characterized by high blast counts in the bone marrow (83%, range 55% - 92%). Ex vivo, leukemic cells grew permanently generating AE/VENTX positive cell lines. RNA-Seq analyses from CD34+ cord blood transduced with VENTX documented 279 differentially expressed genes compared to the empty vector control, comprising pathways belonging to the categories “viral carcinogenesis”, “cytokine-cytokine receptor interaction”, “JAK-STAT signaling”, “cancer”, “signaling pathways in cancer”, “transcriptional misregulation in cancer” and “Huntington’s disease” in the KEGG analysis. Genes necessary for terminal erythroid differentiation such as the EPO-receptor and GATA1 were downregulated by constitutive VENTX expression.In line with the observation of VENTX induced primitive erythroid expansion in mice, VENTX was highly expressed in patients with primary human erythroleukemias and polycythemia vera. Knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked growth in vitro and engraftment in NSG mice. Overexpression of VENTX impaired expression of genes linked to erythroid differentiation in human stem and progenitor cells.
Conclusion
In summary, these data indicate that aberrant expression of VENTX induces expansion of primitive erythroid cells and collaborates with AML1-ETO in inducing AML in mice.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): Acute myeloid leukemia, AML1-ETO, Homeobox gene, Transcription factor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Homeobox genes are key factors in the development of acute leukemias. So far, little is known about the role of non-clustered homeobox genes such as VENTX. The Vent-like homeobox gene VENTX is a member of the Vent gene family in mammals and is the mammalian homolog of the Xenopus xvent gene. Our group has previously shown that the homeobox gene VENTX shows high and aberrant expression in human acute myeloid leukemia (AML) characterized by the AML1-ETO (AE) fusion (Rawat et al., PNAS 2010).
Aims
With this study, we wanted to test the functional relevance of VENTX in the development of AE positive AML in mice.
Methods
To address this, mice were transplanted with bone marrow progenitor cells retrovirally engineered to express VENTX or AML1-ETO alone or in combination.
Results
Whereas none of the AML1-ETO mice developed any disease, all the recipients of AML1-ETO/VENTX double transduced cells succumbed to AML after a median latency of 334 days (range 19-403 days) post transplantation. Of note, induced AML cases were positive for erythroid markers such as CD71 and Ter119. Strikingly, VENTX alone induced a massive expansion of the primitive erythroid compartment in all transplanted mice. Furthermore, this massive perturbation in differentiation converted into an acute erythroleukemia in a fraction of mice. All leukemias in the AE/VENTX and the VENTX experimental arms were rapidly transplantable with a median latency of 40 days until leukemia induced death, characterized by high blast counts in the bone marrow (83%, range 55% - 92%). Ex vivo, leukemic cells grew permanently generating AE/VENTX positive cell lines. RNA-Seq analyses from CD34+ cord blood transduced with VENTX documented 279 differentially expressed genes compared to the empty vector control, comprising pathways belonging to the categories “viral carcinogenesis”, “cytokine-cytokine receptor interaction”, “JAK-STAT signaling”, “cancer”, “signaling pathways in cancer”, “transcriptional misregulation in cancer” and “Huntington’s disease” in the KEGG analysis. Genes necessary for terminal erythroid differentiation such as the EPO-receptor and GATA1 were downregulated by constitutive VENTX expression.In line with the observation of VENTX induced primitive erythroid expansion in mice, VENTX was highly expressed in patients with primary human erythroleukemias and polycythemia vera. Knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked growth in vitro and engraftment in NSG mice. Overexpression of VENTX impaired expression of genes linked to erythroid differentiation in human stem and progenitor cells.
Conclusion
In summary, these data indicate that aberrant expression of VENTX induces expansion of primitive erythroid cells and collaborates with AML1-ETO in inducing AML in mice.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): Acute myeloid leukemia, AML1-ETO, Homeobox gene, Transcription factor
Abstract: P174
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Homeobox genes are key factors in the development of acute leukemias. So far, little is known about the role of non-clustered homeobox genes such as VENTX. The Vent-like homeobox gene VENTX is a member of the Vent gene family in mammals and is the mammalian homolog of the Xenopus xvent gene. Our group has previously shown that the homeobox gene VENTX shows high and aberrant expression in human acute myeloid leukemia (AML) characterized by the AML1-ETO (AE) fusion (Rawat et al., PNAS 2010).
Aims
With this study, we wanted to test the functional relevance of VENTX in the development of AE positive AML in mice.
Methods
To address this, mice were transplanted with bone marrow progenitor cells retrovirally engineered to express VENTX or AML1-ETO alone or in combination.
Results
Whereas none of the AML1-ETO mice developed any disease, all the recipients of AML1-ETO/VENTX double transduced cells succumbed to AML after a median latency of 334 days (range 19-403 days) post transplantation. Of note, induced AML cases were positive for erythroid markers such as CD71 and Ter119. Strikingly, VENTX alone induced a massive expansion of the primitive erythroid compartment in all transplanted mice. Furthermore, this massive perturbation in differentiation converted into an acute erythroleukemia in a fraction of mice. All leukemias in the AE/VENTX and the VENTX experimental arms were rapidly transplantable with a median latency of 40 days until leukemia induced death, characterized by high blast counts in the bone marrow (83%, range 55% - 92%). Ex vivo, leukemic cells grew permanently generating AE/VENTX positive cell lines. RNA-Seq analyses from CD34+ cord blood transduced with VENTX documented 279 differentially expressed genes compared to the empty vector control, comprising pathways belonging to the categories “viral carcinogenesis”, “cytokine-cytokine receptor interaction”, “JAK-STAT signaling”, “cancer”, “signaling pathways in cancer”, “transcriptional misregulation in cancer” and “Huntington’s disease” in the KEGG analysis. Genes necessary for terminal erythroid differentiation such as the EPO-receptor and GATA1 were downregulated by constitutive VENTX expression.In line with the observation of VENTX induced primitive erythroid expansion in mice, VENTX was highly expressed in patients with primary human erythroleukemias and polycythemia vera. Knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked growth in vitro and engraftment in NSG mice. Overexpression of VENTX impaired expression of genes linked to erythroid differentiation in human stem and progenitor cells.
Conclusion
In summary, these data indicate that aberrant expression of VENTX induces expansion of primitive erythroid cells and collaborates with AML1-ETO in inducing AML in mice.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): Acute myeloid leukemia, AML1-ETO, Homeobox gene, Transcription factor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Homeobox genes are key factors in the development of acute leukemias. So far, little is known about the role of non-clustered homeobox genes such as VENTX. The Vent-like homeobox gene VENTX is a member of the Vent gene family in mammals and is the mammalian homolog of the Xenopus xvent gene. Our group has previously shown that the homeobox gene VENTX shows high and aberrant expression in human acute myeloid leukemia (AML) characterized by the AML1-ETO (AE) fusion (Rawat et al., PNAS 2010).
Aims
With this study, we wanted to test the functional relevance of VENTX in the development of AE positive AML in mice.
Methods
To address this, mice were transplanted with bone marrow progenitor cells retrovirally engineered to express VENTX or AML1-ETO alone or in combination.
Results
Whereas none of the AML1-ETO mice developed any disease, all the recipients of AML1-ETO/VENTX double transduced cells succumbed to AML after a median latency of 334 days (range 19-403 days) post transplantation. Of note, induced AML cases were positive for erythroid markers such as CD71 and Ter119. Strikingly, VENTX alone induced a massive expansion of the primitive erythroid compartment in all transplanted mice. Furthermore, this massive perturbation in differentiation converted into an acute erythroleukemia in a fraction of mice. All leukemias in the AE/VENTX and the VENTX experimental arms were rapidly transplantable with a median latency of 40 days until leukemia induced death, characterized by high blast counts in the bone marrow (83%, range 55% - 92%). Ex vivo, leukemic cells grew permanently generating AE/VENTX positive cell lines. RNA-Seq analyses from CD34+ cord blood transduced with VENTX documented 279 differentially expressed genes compared to the empty vector control, comprising pathways belonging to the categories “viral carcinogenesis”, “cytokine-cytokine receptor interaction”, “JAK-STAT signaling”, “cancer”, “signaling pathways in cancer”, “transcriptional misregulation in cancer” and “Huntington’s disease” in the KEGG analysis. Genes necessary for terminal erythroid differentiation such as the EPO-receptor and GATA1 were downregulated by constitutive VENTX expression.In line with the observation of VENTX induced primitive erythroid expansion in mice, VENTX was highly expressed in patients with primary human erythroleukemias and polycythemia vera. Knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked growth in vitro and engraftment in NSG mice. Overexpression of VENTX impaired expression of genes linked to erythroid differentiation in human stem and progenitor cells.
Conclusion
In summary, these data indicate that aberrant expression of VENTX induces expansion of primitive erythroid cells and collaborates with AML1-ETO in inducing AML in mice.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): Acute myeloid leukemia, AML1-ETO, Homeobox gene, Transcription factor
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