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Mukherjee K , Sha X , Magimaidas A , Maifrede S , Skorski T , Bhatia R , Hoffman B , Liebermann DA
Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia
Oncotarget. 2017 Feb 14;8(7) :10809-10821
PMID: 28086219    PMCID: PMC5355225   
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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/EBPalpha 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.
1949-2553 Mukherjee, Kaushiki Sha, Xiaojin Magimaidas, Andrew Maifrede, Silvia Skorski, Tomasz Bhatia, Ravi Hoffman, Barbara Liebermann, Dan A R01 CA095684/CA/NCI NIH HHS/United States R01 CA162403/CA/NCI NIH HHS/United States Journal Article United States Oncotarget. 2017 Feb 14;8(7):10809-10821. doi: 10.18632/oncotarget.14580.