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2014 ; 13
(11
): 1717-26
Nephropedia Template TP
gab.com Text
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English Wikipedia
Lineage-specific function of Engrailed-2 in the progression of chronic
myelogenous leukemia to T-cell blast crisis
#MMPMID24675889
Abollo-Jiménez F
; Campos-Sánchez E
; Toboso-Navasa A
; Vicente-Dueñas C
; González-Herrero I
; Alonso-Escudero E
; González M
; Segura V
; Blanco O
; Martínez-Climent JA
; Sánchez-García I
; Cobaleda C
Cell Cycle
2014[]; 13
(11
): 1717-26
PMID24675889
show ga
In hematopoietic malignancies, oncogenic alterations interfere with cellular
differentiation and lead to tumoral development. Identification of the proteins
regulating differentiation is essential to understand how they are altered in
malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated
by an alteration taking place in hematopoietic stem cells. CML progresses to a
blast crisis (BC) due to a secondary differentiation block in any of the
hematopoietic lineages. However, the molecular mechanisms of CML evolution to
T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation
patterns in human samples from BC-CML, in order to identify genes whose
expression is epigenetically silenced during progression to T-cell
lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2)
gene becomes methylated in this progression. Afterwards, we demonstrate that En2
is expressed during T-cell development in mice and humans. Finally, we further
show that genetic deletion of En2 in a CML transgenic mouse model induces a
T-cell lineage BC that recapitulates human disease. These results identify En2 as
a new regulator of T-cell differentiation whose disruption induces a malignant
T-cell fate in CML progression, and validate the strategy used to identify new
developmental regulators of hematopoiesis.