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Functional Modeling of Genes Upregulated in Chronic Myeloid Leukemia

Hansen, Nils LU (2013) In Lund University Faculty of Medicine Doctoral Dissertation Series 2013:124.
Abstract
Chronic myeloid leukemia (CML) is caused by the transformation of a primitive hematopoietic cell by the BCR/ABL1 fusion gene that is formed through the chromosomal translocation t(9;22). CML is currently successfully treated with tyrosine kinase inhibitors targeting the ABL1 kinase domain. However, the CML stem cells are insensitive to this drug and a large fraction of patients will have relapse following discontinuation of the drug. Thus, improved therapeutic strategies are needed towards the ultimate goal of curing CML. In Article I, the functional role of supressor of cytokine signaling 2 (SOCS2) in CML and in normal hematopoiesis was investigated. Mice deficient for the Socs2 gene displayed normal steady-state hematopoiesis and... (More)
Chronic myeloid leukemia (CML) is caused by the transformation of a primitive hematopoietic cell by the BCR/ABL1 fusion gene that is formed through the chromosomal translocation t(9;22). CML is currently successfully treated with tyrosine kinase inhibitors targeting the ABL1 kinase domain. However, the CML stem cells are insensitive to this drug and a large fraction of patients will have relapse following discontinuation of the drug. Thus, improved therapeutic strategies are needed towards the ultimate goal of curing CML. In Article I, the functional role of supressor of cytokine signaling 2 (SOCS2) in CML and in normal hematopoiesis was investigated. Mice deficient for the Socs2 gene displayed normal steady-state hematopoiesis and hematopoietic stem cell (HSC) function. Transduction of bone marrow (BM) cells from Socs2-deficient mice with BCR/ABL1 and subsequent transplantation resulted in a CML-like disease indistuingishable from the disease in control mice, suggesting that SOCS2 is dispensible for normal hematopoiesis and CML pathogenesis. In Article II, global gene expression analysis and subsequent flow cytometric analysis of normal and CML BM cells showed that interleukin-1 receptor acessory protein (IL1RAP) was highly upregulated on the cell surface of CML cells, allowing prospective separation of candidate CML stem cells from normal hematopoietic stem cells. The use of a polyclonal IL1RAP antibody enabled antibody-dependent cellular cytotoxicity (ADCC) of CD34+CD38- CML cells in vitro. In Article III, the function of IL1RAP in normal hematopoeisis and in CML was investigated. Mice lacking Il1rap displayed lower myeloid steady-state cell counts. Overexpression of IL1RAP in cord blood cells, followed by transplantation into immunodeficient mice, resulted in increased levels of myelopoeisis. Finally, CD34+CD38- CML cells were found to respond strongly to IL1B stimulation in vitro. Together, the results suggest that IL1RAP is a promising target for novel therapeutic approaches in CML. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD, PhD Bhatia, Ravi, City of Hope National Medical Center, California, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Chronic myeloid leukemia, SOCS2, IL1RAP, BCR/ABL1, leukemia models
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2013:124
pages
70 pages
publisher
Division of Clinical Genetics, Lund University
defense location
Segerfalksalen, BMC, Lund
defense date
2013-11-22 13:00:00
ISSN
1652-8220
ISBN
978-91-87449-97-0
language
English
LU publication?
yes
id
9af19f93-0a9b-434d-8d28-279f8acd4808 (old id 4143998)
date added to LUP
2016-04-01 13:34:11
date last changed
2019-05-22 04:16:07
@phdthesis{9af19f93-0a9b-434d-8d28-279f8acd4808,
  abstract     = {{Chronic myeloid leukemia (CML) is caused by the transformation of a primitive hematopoietic cell by the BCR/ABL1 fusion gene that is formed through the chromosomal translocation t(9;22). CML is currently successfully treated with tyrosine kinase inhibitors targeting the ABL1 kinase domain. However, the CML stem cells are insensitive to this drug and a large fraction of patients will have relapse following discontinuation of the drug. Thus, improved therapeutic strategies are needed towards the ultimate goal of curing CML. In Article I, the functional role of supressor of cytokine signaling 2 (SOCS2) in CML and in normal hematopoiesis was investigated. Mice deficient for the Socs2 gene displayed normal steady-state hematopoiesis and hematopoietic stem cell (HSC) function. Transduction of bone marrow (BM) cells from Socs2-deficient mice with BCR/ABL1 and subsequent transplantation resulted in a CML-like disease indistuingishable from the disease in control mice, suggesting that SOCS2 is dispensible for normal hematopoiesis and CML pathogenesis. In Article II, global gene expression analysis and subsequent flow cytometric analysis of normal and CML BM cells showed that interleukin-1 receptor acessory protein (IL1RAP) was highly upregulated on the cell surface of CML cells, allowing prospective separation of candidate CML stem cells from normal hematopoietic stem cells. The use of a polyclonal IL1RAP antibody enabled antibody-dependent cellular cytotoxicity (ADCC) of CD34+CD38- CML cells in vitro. In Article III, the function of IL1RAP in normal hematopoeisis and in CML was investigated. Mice lacking Il1rap displayed lower myeloid steady-state cell counts. Overexpression of IL1RAP in cord blood cells, followed by transplantation into immunodeficient mice, resulted in increased levels of myelopoeisis. Finally, CD34+CD38- CML cells were found to respond strongly to IL1B stimulation in vitro. Together, the results suggest that IL1RAP is a promising target for novel therapeutic approaches in CML.}},
  author       = {{Hansen, Nils}},
  isbn         = {{978-91-87449-97-0}},
  issn         = {{1652-8220}},
  keywords     = {{Chronic myeloid leukemia; SOCS2; IL1RAP; BCR/ABL1; leukemia models}},
  language     = {{eng}},
  publisher    = {{Division of Clinical Genetics, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Functional Modeling of Genes Upregulated in Chronic Myeloid Leukemia}},
  url          = {{https://lup.lub.lu.se/search/files/3452298/4144000.pdf}},
  volume       = {{2013:124}},
  year         = {{2013}},
}