Overexpression of LMO2 causes aberrant human T-Cell development in vivo by three potentially distinct cellular mechanisms.
Overexpression of LMO2 is known to be one of the causes of T-cell acute lymphoblastic leukemia (T-ALL) development; however, the mechanisms behind its oncogenic activity are incompletely understood. LMO2-overexpressing transgenic mouse models suggest an accumulation of immature T-cell progenitors in the thymus as the main preleukemic event. The effects of LMO2 overexpression on human T-cell development in vivo are unknown. Here, we report studies of a humanized mouse model transplanted with LMO2-transduced human hematopoietic stem/progenitor cells. The effects of LMO2 overexpression were confined to the T-cell lineage; however, initially, multipotent cells were transduced. Three effects of LMO2 on human T-cell development were observed: (1) a block at the double-negative/immature single-positive stage, (2) an accumulation of CD4(+)CD8(+) double-positive CD3(-) cells, and (3) an altered CD8/CD4 ratio with enhanced peripheral T lymphocytes. Microarray analysis of sorted double-positive cells overexpressing LMO2 led to the identification of an LMO2 gene set that clustered with human T-ALL patient samples of the described "proliferative" cluster. In this article, we demonstrate previously unrecognized mechanisms by which LMO2 alters human T-cell development in vivo; these mechanisms correlate with human T-ALL leukemogenesis.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Anna-Sophia
AS
Wiekmeijer
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Karin
K
Pike-Overzet
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Martijn H
MH
Brugman
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Marja C J A
MCJA
van Eggermond
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Martijn
M
Cordes
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Edwin F E
EFE
de Haas
Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
Yunlei
Y
Li
Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
Edwin
E
Oole
Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
Wilfred F J
WFJ
van IJcken
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Division of Hematology/Oncology, Hospital for Sick Children/University of Toronto, Toronto, Canada.
R Maarten
RM
Egeler
Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
Jules P
JP
Meijerink
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: f.j.t.staal@lumc.nl.
Frank J T
FJT
Staal
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D015870:Gene Expression; D020869:Gene Expression Profiling; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins