Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia

// Kaushiki Mukherjee 1,* , Xiaojin Sha 1,* , Andrew Magimaidas 1,3,* , Silvia Maifrede 1,2 , Tomasz Skorski 1,2 , Ravi Bhatia 4 , Barbara Hoffman 1,5 and Dan A. Liebermann 1,5 1 Fels Institute for Cancer Research and Molecular Biology, Philadelphia, PA, USA 2 Department of Microbiology and Immunology, Temple University, Philadelphia, PA, USA 3 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 4 Division of Hematology and Oncology, University of Alabama, Tuscaloosa, AL, USA 5 Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, PA, USA * These authors have contributed equally to this work Correspondence to: Dan A. Liebermann, email: // Keywords : Gadd45a, chronic myelogenous leukemia, stress response protein, tumor suppressor Received : September 23, 2016 Accepted : November 23, 2016 Published : January 10, 2017 Abstract The Gadd45a stress sensor gene is a member in the Gadd45 family of genes that includes Gadd45b & Gadd45g. To investigate the effect of GADD45A in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45a null myeloid progenitors transduced with a retroviral vector expressing the 210-kD BCR-ABL fusion oncoprotein. Loss of Gadd45a was observed to accelerate BCR-ABL driven CML resulting in the development of a more aggressive disease, a significantly shortened median mice survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin- cKit+Sca+). GADD45A deficient progenitors expressing BCR-ABL exhibited increased proliferation and decreased apoptosis relative to WT counterparts, which was associated with enhanced PI3K-AKT-mTOR-4E-BP1 signaling, upregulation of p30C/EBPα expression, and hyper-activation of p38 and Stat5. Furthermore, Gadd45a expression in samples obtained from CML patients was upregulated in more indolent chronic phase CML samples and down regulated in aggressive accelerated phase CML and blast crisis CML. These results provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven leukemia and may provide a unique prognostic marker of CML progression.