The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate

Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPα DNA binding via leucine zipper domain interaction

“…In vitro translated C/EBPa, c-Jun, c-JunDRK (deletion of the DNA binding domain), and c-JunDLZ (deletion of the leucine zipper dimerization domain) were generated using Promega in vitro translation kit Rangatia et al, 2002). C/EBPa (SC-61X) antibody and normal rabbit IgG (SC-2027) from Santa Cruz were used for supershift experiments Since C/EBPa is inactivated by BCR-ABL (Perrotti et al, 2002;Schuster et al, 2003), AML1-ETO (Pabst et al, 2001a), PML-RARa (Truong et al, 2003), and through mutation (Pabst et al, 2001b), thus being a common target in myeloid leukemias, we hypothesized that elevated c-Jun expression in AML might inactivate C/EBPa function. We have earlier shown using coimmunoprecipitation and GST pulldown assays that C/ EBPa and c-Jun interact through their leucine zipper domains .…”

“…Thus, we previously reported that C/EBPa (Pabst et al, 2001b) and PU.1 are mutated in AML, and that AML1-ETO in t(8;21)-AML binds to C/EBPa (Pabst et al, 2001b) and PU.1 (Vangala et al, 2003) and blocks their activity via direct protein-protein interactions. Furthermore, the fusion protein BCR-ABL in chronic myeloid leukemia (Perrotti et al, 2002;Schuster et al, 2003) and AML-specific Flt3 mutations (Mizuki et al, 2002) downregulate C/EBPa expression. Thus, inactivation of C/EBPa and PU.1 by direct protein-protein interactions is an arising new mechanism in the pathogenesis of myeloid leukemias.…”

p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription

“…13 BCR-ABL initiates an erythroid program in myeloid leukemic HL-60 cells 14 or induces a reversible block in the granulocytic program of differentiation in 32D cells. 15 In addition, mice engrafted with bone marrow cells infected with a BCR-ABL-encoding retrovirus develop multiple hematopoietic disorders, including a clonal hyperproliferation of erythroid and/ or mast cells. 13,16,17 Moreover, erythroid cells are generated from human cord blood CD34 þ -derived granulopoietic progenitors transduced with p210 BCR-ABL .…”

Robust in vivo differentiation of t(8;21)-positive acute myeloid leukemia blasts to neutrophilic granulocytes induced by treatment with dasatinib

“…As induction of granulocytic differentiation by imatinib has been described via upregulation of CAAT-enhancer binding protein-a (C/EBPa), 7,8 immunohistochemistry for C/EBPa expression was performed on BM sections sampled before and during dasatinib treatment, with C/EBPa expression being detectable only after initiation of dasatinib treatment (Figure 1e).…”