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/EBPa 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.
Highlights
The GADD45 family of proteins (GADD45A, GADD45B, and GADD45G) act as stress sensors in response to various physiological and environmental stressors, including oncogenic stress [1,2,3,4,5] Gadd45 function is mediated via interaction of its cognate protein with partner proteins including PCNA, cdk1/cyclinB1 complex, p21, MEKK4, MKK7, and p38, to modulate cell cycle regulation [6] [7], DNA replication/repair [8, 9] [10] and cell survival [11]
To investigate the effect of loss of Gadd45a on BCR-ABL driven leukemia, bone marrow transplantation (BMT) using WT and Gadd45a knockout (KO) bone marrow (BM) cells transduced with the BCR-ABL oncoprotein was performed
White blood cell (WBC) counts in peripheral blood were significantly increased in Gadd45a-/-/BCR-ABL recipients compared to WT/BCR-ABL recipients (Figure 1C), and hematopathological analysis revealed this was associated with a dramatic increase in number of dysplastic granulocytes (Figure 1D)
Summary
The GADD45 family of proteins (GADD45A, GADD45B, and GADD45G) act as stress sensors in response to various physiological and environmental stressors, including oncogenic stress [1,2,3,4,5] Gadd function is mediated via interaction of its cognate protein with partner proteins including PCNA, cdk1/cyclinB1 complex, p21, MEKK4, MKK7, and p38, to modulate cell cycle regulation [6] [7], DNA replication/repair [8, 9] [10] and cell survival [11]. The Philadelphia chromosome (Ph) arises from a balanced translocation involving chromosomes 9 and 22 [19] This translocation forms the fusion oncoprotein, a constitutionally active tyrosine kinase BCR-ABL, www.impactjournals.com/oncotarget which has been causatively linked to the development of Chronic Myelogenous Leukemia (CML). CML is characterized by the progression from an indolent ‘chronic phase’ (CML-CP), a phase in which mature granulocytes hyperproliferate, to the aggressive and fatal ‘blast crisis’ (CML-BC) marked by the clonal expansion of differentiation-arrested immature blasts [20,21,22]
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