title: Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia.
abstract: Recent discoveries have led to the testing of novel targeted therapies for the treatment of acute myeloid leukemia (AML). To better inform the results of clinical trials, there is a need to identify and systematically assess biomarkers of response and pharmacodynamic markers of successful target engagement. Spleen tyrosine kinase (SYK) is a candidate therapeutic target in AML. Small-molecule inhibitors of SYK induce AML differentiation and impair leukemia progression in preclinical studies. However, tools to predict response to SYK inhibition and to routinely evaluate SYK activation in primary patient samples have been lacking. In this study we quantified phosphorylated SYK (P-SYK) in AML cell lines and establish that increasing levels of baseline P-SYK are correlated with an increasing sensitivity to small-molecule inhibitors targeting SYK. In addition, we found that pharmacological inhibition of SYK activity extinguishes P-SYK expression as detected by an immunohistochemical (IHC) test. Quantitative analysis of P-SYK expression by the IHC test in a series of 70 primary bone marrow biopsy specimens revealed a spectrum of P-SYK expression across AML cases and that high P-SYK expression is associated with unfavourable outcome independent of age, cytogenetics, and white blood cell count. This study thus establishes P-SYK as a critical biomarker in AML that identifies tumors sensitive to SYK inhibition, identifies an at-risk patient population, and allows for the monitoring of target inhibition during treatment.
authors: Department of Histopathology, Manchester Royal Infirmary, Manchester, UK.
authors: Katalin
authors: K
authors: Boros
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.|INSERM U1065, Team 2, C3M, Nice, France.
authors: Alexandre
authors: A
authors: Puissant
authors: The Medical School, The University of Manchester, Manchester, UK.
authors: Morgan
authors: M
authors: Back
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
authors: Gabriela
authors: G
authors: Alexe
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
authors: Christopher F
authors: CF
authors: Bassil
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors: Papiya
authors: P
authors: Sinha
authors: Department of Haematology, Manchester Royal Infirmary, Manchester, UK.
authors: Eleni
authors: E
authors: Tholouli
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
authors: Kimberly
authors: K
authors: Stegmaier
authors: Institute of Cancer Sciences, The University of Manchester, Manchester, UK.
authors: Richard J
authors: RJ
authors: Byers
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors: Scott J
authors: SJ
authors: Rodig
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001856:Bone Marrow Examination; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D000072377:Syk Kinase; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: AML; SYK tyrosine kinase; clinical trials; poor prognosis; tissue microarray