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Notch signaling in acute promyelocytic leukemia
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Journal Article
Notch signaling in acute promyelocytic leukemia
2013
Overview
Acute promyelocytic leukemia (APL) is initiated by the
PML-RARA
(
PR
) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (
JAG1
). In this study, we used a series of bioinformatic,
in vitro
, and
in vivo
assays to assess the role of Notch signaling in human APL samples, and in a
PML-RARA
knock-in mouse model of APL
(Ctsg-PML-RARA)
. We identified a Notch expression signature in both human primary APL cells and in Kit+Lin−Sca1+ cells from pre-leukemic
Ctsg-PML-RARA
mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic
Ctsg-PML-RARA
mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth
in vitro
when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth
in vivo
in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for
PML-RARA
-mediated leukemogenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 692/420
/ Animals
/ Ataxin
/ Bone Marrow Cells - cytology
/ Bone Marrow Cells - metabolism
/ Calcium-Binding Proteins - genetics
/ Calcium-Binding Proteins - metabolism
/ Cellular signal transduction
/ Female
/ Genomes
/ Humans
/ Intercellular Signaling Peptides and Proteins - genetics
/ Intercellular Signaling Peptides and Proteins - metabolism
/ Leukemia
/ Leukemia, Promyelocytic, Acute - genetics
/ Leukemia, Promyelocytic, Acute - metabolism
/ Leukemia, Promyelocytic, Acute - pathology
/ Ligands
/ Male
/ Medicine
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Oncogene Proteins, Fusion - genetics
/ Oncology
/ Receptor, Notch1 - metabolism
/ Signal Transduction - genetics
/ Signal Transduction - physiology
/ Tumors
