ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia

// Carolina Yaeko Namasu 1 , Christiane Katzerke 1 , Daniela Brauer-Hartmann 1 , Alexander Arthur Wurm 1 , Dennis Gerloff 2 , Jens-Uwe Hartmann 1 , Sebastian Schwind 1 , Carsten Muller-Tidow 3 , Nadja Hilger 4 , Stephan Fricke 4 , Maximilian Christopeit 5 , Dietger Niederwieser 1 and Gerhard Behre 1 1 Division of Hematology and Oncology, University Hospital Leipzig, Leipzig, Germany 2 Division of Dermatology and Venereology, University Hospital Halle, Halle, Germany 3 Division of Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany 4 Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany 5 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Gerhard Behre, email: gerhard.behre@medizin.uni-leipzig.de Keywords: acute myeloid leukemia, ABR, C/EBPα, myelopoiesis, prognostic Received: April 04, 2017      Accepted: September 22, 2017      Published: October 26, 2017 ABSTRACT Active BCR related ( ABR ) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia. BCR gene, closely related to ABR, acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with ABR . Evidence for a putative tumor suppressor role of ABR has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of ABR in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPα, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPα in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high ABR expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that ABR expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of ABR and underline its potential role in leukemia therapeutic strategies.