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Leukemia. 2014 Jun;28(6):1252-1258. doi: 10.1038/leu.2013.371. Epub 2013 Dec 11.

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy.

Author information

1
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
2
The Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
3
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
4
University of Alabama at Birmingham, Birmingham, AL, USA.
5
The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
6
University of Iowa, Iowa City, IA, USA.
7
Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
8
North Shore University Hospital, Manhasset, NY, USA.
9
Dana-Farber Cancer Institute, Boston, MA, USA.
#
Contributed equally

Abstract

Emerging data demonstrate important roles for the TYRO3/AXL/MERTK receptor tyrosine kinase (TAM RTK) family in diverse cancers. We investigated the prognostic relevance of GAS6 expression, encoding the common TAM RTK ligand, in 270 adults (n=71 aged<60 years; n=199 aged ⩾60 years) with de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients expressing GAS6 (GAS6+), especially those aged ⩾60 years, more often failed to achieve a complete remission (CR). In all patients, GAS6+ patients had shorter disease-free (DFS) and overall (OS) survival than patients without GAS6 expression (GAS6-). After adjusting for other prognostic markers, GAS6+ predicted CR failure (P=0.02), shorter DFS (P=0.004) and OS (P=0.04). To gain further biological insights, we derived a GAS6-associated gene-expression signature (P<0.001) that in GAS6+ patients included overexpressed BAALC and MN1, known to confer adverse prognosis in CN-AML, and overexpressed CXCL12, encoding stromal cell-derived factor, and its receptor genes, chemokine (C-X-C motif) receptor 4 (CXCR4) and CXCR7. This study reports for the first time that GAS6 expression is an adverse prognostic marker in CN-AML. Although GAS6 decoy receptors are not yet available in the clinic for GAS6+ CN-AML therapy, potential alternative therapies targeting GAS6+-associated pathways, for example, CXCR4 antagonists, may be considered for GAS6+ patients to sensitize them to chemotherapy.

PMID:
24326683
PMCID:
PMC4047202
DOI:
10.1038/leu.2013.371
[Indexed for MEDLINE]
Free PMC Article

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