title: GAS6 expression identifies high-risk adult AML patients: potential implications for therapy.
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.
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Susan P
authors: SP
authors: Whitman
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|The Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors: Jessica
authors: J
authors: Kohlschmidt
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|The Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors: Kati
authors: K
authors: Maharry
authors: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
authors: Stefano
authors: S
authors: Volinia
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Krzysztof
authors: K
authors: Mrózek
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|The Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors: Deedra
authors: D
authors: Nicolet
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Sebastian
authors: S
authors: Schwind
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Heiko
authors: H
authors: Becker
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Klaus H
authors: KH
authors: Metzeler
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Jason H
authors: JH
authors: Mendler
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Ann-Kathrin
authors: AK
authors: Eisfeld
authors: University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Andrew J
authors: AJ
authors: Carroll
authors: The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
authors: Bayard L
authors: BL
authors: Powell
authors: University of Iowa, Iowa City, IA, USA.
authors: Thomas H
authors: TH
authors: Carter
authors: Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors: Maria R
authors: MR
authors: Baer
authors: North Shore University Hospital, Manhasset, NY, USA.
authors: Jonathan E
authors: JE
authors: Kolitz
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Il-Kyoo
authors: IK
authors: Park
authors: Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Richard M
authors: RM
authors: Stone
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Michael A
authors: MA
authors: Caligiuri
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Guido
authors: G
authors: Marcucci
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors: Clara D
authors: CD
authors: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D054387:Receptors, CXCR / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D015996:Survival Rate; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000099255:Growth Arrest-Specific Protein 6; C501896:ACKR3 protein, human; C442828:BAALC protein, human; C527276:CXCR4 protein, human; C506524:MN1 protein, human