HHEX TRANSFORMS PROMYELOCYTES AND COOPERATES WITH FACTOR INDEPENDENCE TO CAUSE PROMYELOCYTIC LEUKEMIA IN MICE
(Abstract release date: 05/19/16)
EHA Library. Jackson J. 06/10/16; 133164; P176
Disclosure(s): Nothing to disclose.
Mr. Jacob T Jackson
Contributions
Contributions
Abstract
Abstract: P176
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The transcription factor Hhex (Hematopoietically-expressed homeobox gene) is important for lymphoid commitment and causes T-cell leukemia when overexpressed. We have recently found that Hhex is overexpressed in human myeloid leukemias and maintains leukemia stem cell self-renewal in mouse models of AML via repression of Cdkn2a. However, whether Hhex overexpression also affects hematopoietic differentiation is not known.
Aims
The aims of this study are to investigate the effects of high levels of Hhex expression in growth factor independent hematopoietic progenitor cells and the roles of the functional domains of Hhex.
Methods
To study the effects of Hhex on haematopoietic progenitor differentiation, we immature Lin-Sca+Kit+ (LSK) hematopoietic progenitors were transduced with retroviruses expressing wild-type and mutant forms of Hhex.
Results
Hhex overexpression in LSK cells caused serial replating of myeloid progenitors and to the rapid establishment of IL-3-dependent promyelocytic cell-lines. Structure function analysis demonstrated a requirement of the DNA binding domain and the N-terminal repressive domains of Hhex in promyelocytic transformation. This included a PML protein interaction domain, although loss of PML failed to prevent Hhex-induced promyelocyte transformation in vitro. RNA-Seq analysis showed that Hhex overexpression leads to repression of myeloid developmental genes including MPO. To test the leukemic potential of Hhex, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell-lines caused rapid promyelocytic leukemia in mice.
Conclusion
In addition to its role in repressing tumor suppressor pathways in myeloid leukemias, overexpression of Hhex causes a differentiation blockade and contributes to promyelocytic leukemia in vivo. As such, Hhex overexpression may contribute to human myeloid leukemias via multiple pathways.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): AML, Hematopoietic stem and progenitor cells, PML, 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 transcription factor Hhex (Hematopoietically-expressed homeobox gene) is important for lymphoid commitment and causes T-cell leukemia when overexpressed. We have recently found that Hhex is overexpressed in human myeloid leukemias and maintains leukemia stem cell self-renewal in mouse models of AML via repression of Cdkn2a. However, whether Hhex overexpression also affects hematopoietic differentiation is not known.
Aims
The aims of this study are to investigate the effects of high levels of Hhex expression in growth factor independent hematopoietic progenitor cells and the roles of the functional domains of Hhex.
Methods
To study the effects of Hhex on haematopoietic progenitor differentiation, we immature Lin-Sca+Kit+ (LSK) hematopoietic progenitors were transduced with retroviruses expressing wild-type and mutant forms of Hhex.
Results
Hhex overexpression in LSK cells caused serial replating of myeloid progenitors and to the rapid establishment of IL-3-dependent promyelocytic cell-lines. Structure function analysis demonstrated a requirement of the DNA binding domain and the N-terminal repressive domains of Hhex in promyelocytic transformation. This included a PML protein interaction domain, although loss of PML failed to prevent Hhex-induced promyelocyte transformation in vitro. RNA-Seq analysis showed that Hhex overexpression leads to repression of myeloid developmental genes including MPO. To test the leukemic potential of Hhex, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell-lines caused rapid promyelocytic leukemia in mice.
Conclusion
In addition to its role in repressing tumor suppressor pathways in myeloid leukemias, overexpression of Hhex causes a differentiation blockade and contributes to promyelocytic leukemia in vivo. As such, Hhex overexpression may contribute to human myeloid leukemias via multiple pathways.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): AML, Hematopoietic stem and progenitor cells, PML, Transcription factor
Abstract: P176
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The transcription factor Hhex (Hematopoietically-expressed homeobox gene) is important for lymphoid commitment and causes T-cell leukemia when overexpressed. We have recently found that Hhex is overexpressed in human myeloid leukemias and maintains leukemia stem cell self-renewal in mouse models of AML via repression of Cdkn2a. However, whether Hhex overexpression also affects hematopoietic differentiation is not known.
Aims
The aims of this study are to investigate the effects of high levels of Hhex expression in growth factor independent hematopoietic progenitor cells and the roles of the functional domains of Hhex.
Methods
To study the effects of Hhex on haematopoietic progenitor differentiation, we immature Lin-Sca+Kit+ (LSK) hematopoietic progenitors were transduced with retroviruses expressing wild-type and mutant forms of Hhex.
Results
Hhex overexpression in LSK cells caused serial replating of myeloid progenitors and to the rapid establishment of IL-3-dependent promyelocytic cell-lines. Structure function analysis demonstrated a requirement of the DNA binding domain and the N-terminal repressive domains of Hhex in promyelocytic transformation. This included a PML protein interaction domain, although loss of PML failed to prevent Hhex-induced promyelocyte transformation in vitro. RNA-Seq analysis showed that Hhex overexpression leads to repression of myeloid developmental genes including MPO. To test the leukemic potential of Hhex, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell-lines caused rapid promyelocytic leukemia in mice.
Conclusion
In addition to its role in repressing tumor suppressor pathways in myeloid leukemias, overexpression of Hhex causes a differentiation blockade and contributes to promyelocytic leukemia in vivo. As such, Hhex overexpression may contribute to human myeloid leukemias via multiple pathways.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): AML, Hematopoietic stem and progenitor cells, PML, 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 transcription factor Hhex (Hematopoietically-expressed homeobox gene) is important for lymphoid commitment and causes T-cell leukemia when overexpressed. We have recently found that Hhex is overexpressed in human myeloid leukemias and maintains leukemia stem cell self-renewal in mouse models of AML via repression of Cdkn2a. However, whether Hhex overexpression also affects hematopoietic differentiation is not known.
Aims
The aims of this study are to investigate the effects of high levels of Hhex expression in growth factor independent hematopoietic progenitor cells and the roles of the functional domains of Hhex.
Methods
To study the effects of Hhex on haematopoietic progenitor differentiation, we immature Lin-Sca+Kit+ (LSK) hematopoietic progenitors were transduced with retroviruses expressing wild-type and mutant forms of Hhex.
Results
Hhex overexpression in LSK cells caused serial replating of myeloid progenitors and to the rapid establishment of IL-3-dependent promyelocytic cell-lines. Structure function analysis demonstrated a requirement of the DNA binding domain and the N-terminal repressive domains of Hhex in promyelocytic transformation. This included a PML protein interaction domain, although loss of PML failed to prevent Hhex-induced promyelocyte transformation in vitro. RNA-Seq analysis showed that Hhex overexpression leads to repression of myeloid developmental genes including MPO. To test the leukemic potential of Hhex, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell-lines caused rapid promyelocytic leukemia in mice.
Conclusion
In addition to its role in repressing tumor suppressor pathways in myeloid leukemias, overexpression of Hhex causes a differentiation blockade and contributes to promyelocytic leukemia in vivo. As such, Hhex overexpression may contribute to human myeloid leukemias via multiple pathways.
Session topic: Acute myeloid leukemia - Biology 1
Keyword(s): AML, Hematopoietic stem and progenitor cells, PML, Transcription factor
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