ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia
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Carolina Yaeko Namasu1, Christiane Katzerke1, Daniela Bräuer-Hartmann1, Alexander Arthur Wurm1, Dennis Gerloff2, Jens-Uwe Hartmann1, Sebastian Schwind1, Carsten Müller-Tidow3, Nadja Hilger4, Stephan Fricke4, Maximilian Christopeit5, Dietger Niederwieser1 and Gerhard Behre1
1Division of Hematology and Oncology, University Hospital Leipzig, Leipzig, Germany
2Division of Dermatology and Venereology, University Hospital Halle, Halle, Germany
3Division of Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany
4Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
5Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Gerhard Behre, email: [email protected]
Keywords: acute myeloid leukemia, ABR, C/EBPα, myelopoiesis, prognostic
Received: April 04, 2017 Accepted: September 22, 2017 Published: October 26, 2017
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.
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