Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia

// Katalin Boros 1, # , Alexandre Puissant 2, 3, # , Morgan Back 4 , Gabriela Alexe 2 , Christopher F. Bassil 2 , Papiya Sinha 5 , Eleni Tholouli 6 , Kimberly Stegmaier 2, * , Richard J. Byers 7, * , Scott J. Rodig 5, * 1 Department of Histopathology, Manchester Royal Infirmary, Manchester, UK 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA 3 INSERM U1065, Team 2, C3M, Nice, France 4 The Medical School, The University of Manchester, Manchester, UK 5 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA 6 Department of Haematology, Manchester Royal Infirmary, Manchester, UK 7 Institute of Cancer Sciences, The University of Manchester, Manchester, UK # These authors contributed equally to this work * These senior authors contributed equally to the work Correspondence to: Richard J. Byers e-mail: richard.byers@cmft.nhs.uk , e-mail: r.byers@manchester.ac.uk Keywords: SYK tyrosine kinase, AML, poor prognosis, tissue microarray, clinical trials Received: June 17, 2015      Accepted: July 29, 2015      Published: August 11, 2015 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.