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Response mechanisms of normal hematopoietic cells and leukemic cells to genotoxic agents and novel therapeutic strategies

Hedblom, Andreas LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:80.
Abstract (Swedish)
Hematopoiesis is initiated by a rare population of hematopoietic stem cells (HSC) in the bone marrow (BM). HSCs give rise to red blood cells and white blood cells of myeloid and lymphoid lineages. The red blood cells are responsible for transporting oxygen throughout the body, while the myeloid and lymphoid cells are essentially required for immune responses. The HSCs reside in special niches in the bone marrow, and they are able to respond efficiently to external stresses and injury such as blood loss, infection, or damage caused by cytotoxic agents. Tumor cells and its associated microenvironment acquire multiple alterations which render the tumor cells to respond poorly to treatment. My thesis work is focused on several specific... (More)
Hematopoiesis is initiated by a rare population of hematopoietic stem cells (HSC) in the bone marrow (BM). HSCs give rise to red blood cells and white blood cells of myeloid and lymphoid lineages. The red blood cells are responsible for transporting oxygen throughout the body, while the myeloid and lymphoid cells are essentially required for immune responses. The HSCs reside in special niches in the bone marrow, and they are able to respond efficiently to external stresses and injury such as blood loss, infection, or damage caused by cytotoxic agents. Tumor cells and its associated microenvironment acquire multiple alterations which render the tumor cells to respond poorly to treatment. My thesis work is focused on several specific studies: (i) Study the function of Heme oxygenase 1 (HO-1), a key factor that regulates supply and transport of oxygen. HO-1 with its associated carbon monoxide (CO) mediates response of cells to DNA damages caused by irradiation or chemical genotoxic stress. (ii) Study the function of a key cell cycle regulatory gene, cyclin A1 in the regulation of proliferation, differentiation and migration of HSC, and the role of cyclin A1 and MMP9 in mediating response of the HSC and their adjacent BM microenvironment to genotoxic stress caused by irradiation. (iii) Study the role of the key cell cycle regulator CDK1 in mediating treatment response of leukemic cells to all-trans retinoic acid (ATRA). (iv) Characterize the cellular mechanisms of several anticancer drugs, and our newly developed anticancer drug candidate and its selective target PIP5K1a for treatment of metastatic cancer. We have used several sets of knockout mouse models in which HO-1 or cyclin A1 are deleted, either in germ lines or in specific tissues. In addition, we have used tumor xenograft mouse models in which human prostate cancer were implanted and grown in mice. We have also used normal and cancer specimens from patients with leukemia or prostate cancer. A panel of non-malignant and malignant cell lines has been applied in our in vitro functional studies. Our results have shown that mice lacking HO-1 gene has elevated H2AX, and loss of ATM expression and function. Induction of HO-1 expression reduces DNA damages and activates ATM-supported DNA repair via homologous recombination. We have shown that mice lacking cyclin A1 function has increased proliferation of HSC and migratory ability, and also impaired vascular niches. Mice without cyclin A1 function suffer early deaths after irradiation treatment compared to that of the wild-type mice. MMP9 may mediate the response of the BM to irradiation treatment. We further show that CDK1 plays an important role in mediating treatment response to ATRA-induced differentiation and cell cycle arrest. Finally, we show that our newly developed anticancer drug candidate ISA-2011B is a specific PIP5K1α inhibitor. ISA-2011B inhibits growth of invasive prostate cancer cells through its inhibitory effect on PIP5K1α/PI3K/AKT and AR/cell cycle pathways. Taken together, my work provides novel insights into stem cell regeneration and cancer therapy. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Sigvardsson, Mikael, Linköpings Universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Hematopoietic stem cells, genotoxic damage, cell cycle, leukemia, heme oxygenase, differentiation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:80
pages
62 pages
publisher
Experimental cancer research
defense location
Kvinnoklinikens Aula, Jan Waldenströmsgata 47, 21421 Malmö, Sverige
defense date
2014-06-09 13:00
ISSN
1652-8220
ISBN
978-91-7619-009-8
language
English
LU publication?
yes
id
5e5fdce5-c9cf-4165-a6ef-f09b6f7ad0a4 (old id 4498772)
date added to LUP
2014-06-24 15:15:40
date last changed
2016-09-19 08:44:46
@phdthesis{5e5fdce5-c9cf-4165-a6ef-f09b6f7ad0a4,
  abstract     = {Hematopoiesis is initiated by a rare population of hematopoietic stem cells (HSC) in the bone marrow (BM). HSCs give rise to red blood cells and white blood cells of myeloid and lymphoid lineages. The red blood cells are responsible for transporting oxygen throughout the body, while the myeloid and lymphoid cells are essentially required for immune responses. The HSCs reside in special niches in the bone marrow, and they are able to respond efficiently to external stresses and injury such as blood loss, infection, or damage caused by cytotoxic agents. Tumor cells and its associated microenvironment acquire multiple alterations which render the tumor cells to respond poorly to treatment. My thesis work is focused on several specific studies: (i) Study the function of Heme oxygenase 1 (HO-1), a key factor that regulates supply and transport of oxygen. HO-1 with its associated carbon monoxide (CO) mediates response of cells to DNA damages caused by irradiation or chemical genotoxic stress. (ii) Study the function of a key cell cycle regulatory gene, cyclin A1 in the regulation of proliferation, differentiation and migration of HSC, and the role of cyclin A1 and MMP9 in mediating response of the HSC and their adjacent BM microenvironment to genotoxic stress caused by irradiation. (iii) Study the role of the key cell cycle regulator CDK1 in mediating treatment response of leukemic cells to all-trans retinoic acid (ATRA). (iv) Characterize the cellular mechanisms of several anticancer drugs, and our newly developed anticancer drug candidate and its selective target PIP5K1a for treatment of metastatic cancer. We have used several sets of knockout mouse models in which HO-1 or cyclin A1 are deleted, either in germ lines or in specific tissues. In addition, we have used tumor xenograft mouse models in which human prostate cancer were implanted and grown in mice. We have also used normal and cancer specimens from patients with leukemia or prostate cancer. A panel of non-malignant and malignant cell lines has been applied in our in vitro functional studies. Our results have shown that mice lacking HO-1 gene has elevated H2AX, and loss of ATM expression and function. Induction of HO-1 expression reduces DNA damages and activates ATM-supported DNA repair via homologous recombination. We have shown that mice lacking cyclin A1 function has increased proliferation of HSC and migratory ability, and also impaired vascular niches. Mice without cyclin A1 function suffer early deaths after irradiation treatment compared to that of the wild-type mice. MMP9 may mediate the response of the BM to irradiation treatment. We further show that CDK1 plays an important role in mediating treatment response to ATRA-induced differentiation and cell cycle arrest. Finally, we show that our newly developed anticancer drug candidate ISA-2011B is a specific PIP5K1α inhibitor. ISA-2011B inhibits growth of invasive prostate cancer cells through its inhibitory effect on PIP5K1α/PI3K/AKT and AR/cell cycle pathways. Taken together, my work provides novel insights into stem cell regeneration and cancer therapy.},
  author       = {Hedblom, Andreas},
  isbn         = {978-91-7619-009-8},
  issn         = {1652-8220},
  keyword      = {Hematopoietic stem cells,genotoxic damage,cell cycle,leukemia,heme oxygenase,differentiation},
  language     = {eng},
  pages        = {62},
  publisher    = {Experimental cancer research},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Response mechanisms of normal hematopoietic cells and leukemic cells to genotoxic agents and novel therapeutic strategies},
  volume       = {2014:80},
  year         = {2014},
}