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Cell Stem Cell. 2015 Aug 6;17(2):152-164. doi: 10.1016/j.stem.2015.06.006. Epub 2015 Jul 23.

Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.

Author information

1
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
2
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Asan-si, Chungcheongnamdo 336-745, South Korea.
3
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
4
Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
5
Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857.
6
Clinical Research Division, Fred Hutchinson Cancer Research Center, WA 98109, USA.
7
Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
8
Computational Science Research Center and Biomedical Informatics Research Center, San Diego State University, San Diego, CA 92182, USA.
9
Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
10
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
11
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
#
Contributed equally

Abstract

Acute Myelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease. Here, we show that Tetraspanin 3 is a target of the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockout mice that were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 is also important in human disease. As part of the mechanism, we show that Tspan3 deficiency disabled responses to CXCL12/SDF-1 and led to defects in AML localization within the niche. These identify Tspan3 as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis.

PMID:
26212080
PMCID:
PMC4664079
DOI:
10.1016/j.stem.2015.06.006
[Indexed for MEDLINE]
Free PMC Article

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