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

• Published in: Leukemia Vol. 28; no. 6; pp. 1252 - 1258
• Main Authors: Whitman, S P, Kohlschmidt, J, Maharry, K, Volinia, S, Mrózek, K, Nicolet, D, Schwind, S, Becker, H, Metzeler, K H, Mendler, J H, Eisfeld, A-K, Carroll, A J, Powell, B L, Carter, T H, Baer, M R, Kolitz, J E, Park, I-K, Stone, R M, Caligiuri, M A, Marcucci, G, Bloomfield, C D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2014; Nature Publishing Group
• Subjects: 692/53/2422; 692/699/67/1059/99; 692/699/67/1990/283/1897; Acute myeloid leukemia; Adolescent; Adult; Adults; Aged; Aged, 80 and over; Antagonists; Axl protein; Biomarkers, Tumor - genetics; Cancer; Cancer Research; Cancer therapies; Chemokines; Chemotherapy; Cohort Studies; Critical Care Medicine; CXCL12 protein; CXCR4 protein; Cytogenetic Analysis; Female; Follow-Up Studies; Gene expression; Gene Expression Profiling; Genes; Health aspects; Hematology; Hospitals; Humans; Intensive; Intercellular Signaling Peptides and Proteins - genetics; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - therapy; Ligands; Male; Markers; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neoplasm Proteins - genetics; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Patients; Prognosis; Protein-tyrosine kinase receptors; Receptors; Receptors, CXCR - genetics; Receptors, CXCR4 - genetics; Remission; Remission (Medicine); Survival Rate; Tumor Suppressor Proteins - genetics; Tyrosine; Young Adult; United States; United States > US; Ohio; acute myeloid leukemia; GAS6; prognosis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.371

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.