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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.

SUBMITTER: Whitman SP

PROVIDER: S-EPMC4047202 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Whitman Susan P SP Kohlschmidt Jessica J Maharry Kati K Volinia Stefano S Mrózek Krzysztof K Nicolet Deedra D Schwind Sebastian S Becker Heiko H Metzeler Klaus H KH Mendler Jason H JH Eisfeld Ann-Kathrin AK Carroll Andrew J AJ Powell Bayard L BL Carter Thomas H TH Baer Maria R MR Kolitz Jonathan E JE Park Il-Kyoo IK Stone Richard M RM Caligiuri Michael A MA Marcucci Guido G Bloomfield Clara D CD

Leukemia 20131211 6

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+ pat ...[more]

PMID: 24326683

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

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

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