Enhanced expression of the sphingosine-1-phosphate-receptor-3 causes acute myelogenous leukemia in mice

Acute myeloid leukemia (AML) carries a 10–100 fold lower mutational burden than other neoplastic entities. Mechanistic explanations for why a low number of mutations suffice to induce leukemogenesis are therefore required. Here we demonstrate that transgenic overexpression of the wild type sphingosi...

Full description

Saved in:
Bibliographic Details
Published in:Leukemia 2020-03, Vol.34 (3), p.721-734
Main Authors: Vorbach, Samuel, Gründer, Albert, Zhou, Fengbiao, Koellerer, Christoph, Jutzi, Jonas S., Simoni, Manuela, Riccetti, Laura, Valk, Peter J., Sanders, Mathijs A., Müller-Tidow, Carsten, Nofer, Jerzy-Roch, Pahl, Heike L., Potì, Francesco
Format: Article
Language:English
Subjects:
13
13/100
42
64/60
692/308/575
692/699/67/70
Acute myeloid leukemia
Animals
Blood cells
Cancer
Cancer Research
Cell receptors
Critical Care Medicine
Fingolimod Hydrochloride - pharmacology
Gene expression
Gene Expression Regulation, Leukemic
Genetic transformation
Health aspects
Hematology
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
Humans
Intensive
Internal Medicine
Leukemia
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - therapy
Leukemogenesis
Medicine
Medicine & Public Health
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Myeloid leukemia
Oncology
Oncology, Experimental
Peripheral blood
Receptors
Signal Transduction
Signaling
Sphingosine 1-phosphate
Sphingosine-1-Phosphate Receptors - genetics
Sphingosine-1-Phosphate Receptors - metabolism
Spleen
Stem cell transplantation
Stem cells
Transcriptome
Transgenes
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Acute myeloid leukemia (AML) carries a 10–100 fold lower mutational burden than other neoplastic entities. Mechanistic explanations for why a low number of mutations suffice to induce leukemogenesis are therefore required. Here we demonstrate that transgenic overexpression of the wild type sphingosine-1-phosphate receptor 3 (S1P 3 ) in murine hematopoietic stem cells is sufficient to induce a transplantable myeloid leukemia. In contrast, S1P 3 expression in more mature compartments does not cause malignant transformation. Treatment with the sphingosine phosphate receptor modulator Fingolimod, which prevents receptor signaling, normalized peripheral blood cell counts and reduced spleen sizes in S1P 3 expressing mice. Gene expression analyses in AML patients revealed elevated S1P 3 expression specifically in two molecular subclasses. Our data suggest a previously unrecognized contribution of wild type S1P 3 signaling to leukemogenesis that warrants the exploration of S1P 3 antagonists in preclinical AML models.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-019-0577-7