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Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice

Ågerstam, Helena LU ; Järås, Marcus LU ; Andersson, Anna LU ; Johnels, Petra LU ; Hansen, Nils LU ; Lassen, Carin LU ; Rissler, Marianne LU ; Gisselsson Nord, David LU ; Olofsson, Tor LU and Richter, Johan LU , et al. (2010) In Blood 116(12). p.2103-2111
Abstract
The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34(+) cells from umbilicalcord blood leads to increased cellular proliferation and differentiation... (More)
The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34(+) cells from umbilicalcord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1 or BCR/FGFR1 in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1 fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder. (Blood. 2010;116(12):2103-2111) (Less)
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Blood
volume
116
issue
12
pages
2103 - 2111
publisher
American Society of Hematology
external identifiers
  • wos:000282137300018
  • pmid:20554971
  • scopus:77957196376
ISSN
1528-0020
DOI
10.1182/blood-2009-05-217182
language
English
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yes
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79d66993-b7b1-4025-aa68-5c958d8b119a (old id 1695454)
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2010-10-25 19:53:10
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2018-05-29 09:43:03
@article{79d66993-b7b1-4025-aa68-5c958d8b119a,
  abstract     = {The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34(+) cells from umbilicalcord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1 or BCR/FGFR1 in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1 fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder. (Blood. 2010;116(12):2103-2111)},
  author       = {Ågerstam, Helena and Järås, Marcus and Andersson, Anna and Johnels, Petra and Hansen, Nils and Lassen, Carin and Rissler, Marianne and Gisselsson Nord, David and Olofsson, Tor and Richter, Johan and Fan, Xiaolong and Ehinger, Mats and Fioretos, Thoas},
  issn         = {1528-0020},
  language     = {eng},
  number       = {12},
  pages        = {2103--2111},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice},
  url          = {http://dx.doi.org/10.1182/blood-2009-05-217182},
  volume       = {116},
  year         = {2010},
}