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Molecular and functional studies of ABL1 and FGFR1 fusion oncogenes in myeloproliferative neoplasms

Ågerstam, Helena LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:104.
Abstract
The tyrosine kinase encoding genes ABL1 and FGFR1 are involved in fusion genes underlying the myeloproliferative neoplasms chronic myeloid leukemia (CML) and the 8p11-myeloproliferative syndrome (EMS). CML and EMS are both myeloproliferative disorders with an initiating, relatively indolent, chronic phase that after some time progresses into acute myeloid or lymphoid leukemia. The mechanisms underlying disease progression are currently unknown, but additional genetic aberrations are commonly found in the progressed phase. The general aim of this thesis was to study BCR/ABL1 and FGFR1 fusion oncogenes in a relevant cellular context, that of primary human hematopoietic cells, in order to increase our understanding of disease mechanisms... (More)
The tyrosine kinase encoding genes ABL1 and FGFR1 are involved in fusion genes underlying the myeloproliferative neoplasms chronic myeloid leukemia (CML) and the 8p11-myeloproliferative syndrome (EMS). CML and EMS are both myeloproliferative disorders with an initiating, relatively indolent, chronic phase that after some time progresses into acute myeloid or lymphoid leukemia. The mechanisms underlying disease progression are currently unknown, but additional genetic aberrations are commonly found in the progressed phase. The general aim of this thesis was to study BCR/ABL1 and FGFR1 fusion oncogenes in a relevant cellular context, that of primary human hematopoietic cells, in order to increase our understanding of disease mechanisms underlying the development of CML and EMS. In Article I, a secondary translocation between chromosomes 9 and 21, identified in the leukemic cells from a patient in the progressed phase of EMS, was investigated. The translocation was found to result in a truncated RUNX1 gene, suggesting that haploinsufficiency for RUNX1 could be a mechanism behind disease progression in EMS. It was also found that trisomy 21 is a common secondary change in EMS. In Article II, two variants of BCR/ABL1, P190 and P210, were retrovirally expressed in cord-blood derived human CD34-positive cells. Both variants induced erythroid expansion, increased proliferation, and similar gene expression profiles, indicating that P190 and P210 BCR/ABL1 have a similar mode of action. These results indirectly support the theory that the difference in disease manifestation between P190 and P210 BCR/ABL1 depends on separate cellular origins rather than intrinsic differences of the two fusion proteins. In Article III, retroviral expression of BCR/FGFR1 or ZMYM2/FGFR1 in human CD34-positive cells resulted in increased cellular proliferation and erythroid expansion, in similar to the effects caused by BCR/ABL1. Transplantation of BCR/FGFR1- and ZMYM2/FGFR1-expressing cells into immunodeficient mice resulted in engraftment of human cells in the mouse bone marrow. The human cells differentiated into a myeloid and erythroid direction. Both fusion genes induced similar EMS-like disorders in transplanted mice, with eosinophilia, splenomegaly, and accumulation of blasts. The established in-vivo model of EMS should constitute a valuable tool for obtaining further insights into FGFR1 fusion gene mediated leukemogenesis and for the development and evaluation of new treatment strategies in EMS. (Less)
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author
supervisor
opponent
  • Mulloy, James, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Hospital Medical Center, Cincinnati, USA
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:104
pages
64 pages
publisher
Section of clinical genetics
defense location
Föreläsningssal F3, Universitetssjukhuset i Lund
defense date
2010-11-11 09:00
ISSN
1652-8220
ISBN
978-91-86671-20-4
language
English
LU publication?
yes
id
53fc554b-72f3-480b-88fc-fbfa8b42dd6b (old id 1692678)
date added to LUP
2010-10-21 11:18:41
date last changed
2018-05-29 09:52:27
@phdthesis{53fc554b-72f3-480b-88fc-fbfa8b42dd6b,
  abstract     = {The tyrosine kinase encoding genes ABL1 and FGFR1 are involved in fusion genes underlying the myeloproliferative neoplasms chronic myeloid leukemia (CML) and the 8p11-myeloproliferative syndrome (EMS). CML and EMS are both myeloproliferative disorders with an initiating, relatively indolent, chronic phase that after some time progresses into acute myeloid or lymphoid leukemia. The mechanisms underlying disease progression are currently unknown, but additional genetic aberrations are commonly found in the progressed phase. The general aim of this thesis was to study BCR/ABL1 and FGFR1 fusion oncogenes in a relevant cellular context, that of primary human hematopoietic cells, in order to increase our understanding of disease mechanisms underlying the development of CML and EMS. In Article I, a secondary translocation between chromosomes 9 and 21, identified in the leukemic cells from a patient in the progressed phase of EMS, was investigated. The translocation was found to result in a truncated RUNX1 gene, suggesting that haploinsufficiency for RUNX1 could be a mechanism behind disease progression in EMS. It was also found that trisomy 21 is a common secondary change in EMS. In Article II, two variants of BCR/ABL1, P190 and P210, were retrovirally expressed in cord-blood derived human CD34-positive cells. Both variants induced erythroid expansion, increased proliferation, and similar gene expression profiles, indicating that P190 and P210 BCR/ABL1 have a similar mode of action. These results indirectly support the theory that the difference in disease manifestation between P190 and P210 BCR/ABL1 depends on separate cellular origins rather than intrinsic differences of the two fusion proteins. In Article III, retroviral expression of BCR/FGFR1 or ZMYM2/FGFR1 in human CD34-positive cells resulted in increased cellular proliferation and erythroid expansion, in similar to the effects caused by BCR/ABL1. Transplantation of BCR/FGFR1- and ZMYM2/FGFR1-expressing cells into immunodeficient mice resulted in engraftment of human cells in the mouse bone marrow. The human cells differentiated into a myeloid and erythroid direction. Both fusion genes induced similar EMS-like disorders in transplanted mice, with eosinophilia, splenomegaly, and accumulation of blasts. The established in-vivo model of EMS should constitute a valuable tool for obtaining further insights into FGFR1 fusion gene mediated leukemogenesis and for the development and evaluation of new treatment strategies in EMS.},
  author       = {Ågerstam, Helena},
  isbn         = {978-91-86671-20-4},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {64},
  publisher    = {Section of clinical genetics},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Molecular and functional studies of ABL1 and FGFR1 fusion oncogenes in myeloproliferative neoplasms},
  volume       = {2010:104},
  year         = {2010},
}