C/EBPß promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion.

ABSTRACT

The BCR-ABL fusion oncoprotein accelerates differentiation and proliferation of myeloid cells during the chronic phase of chronic myeloid leukemia (CP-CML). Here, the role of CCAAT/enhancer binding protein ß (C/EBPß), a regulator for 'emergency granulopoiesis,' in the pathogenesis of CP-CML was examined. C/EBPß expression was upregulated in Lineage(-) CD34(+) CD38(-) hematopoietic stem cells (HSCs) and myeloid progenitors isolated from bone marrow of patients with CP-CML. In EML cells, a mouse HSC line, BCR-ABL upregulated C/EBPß, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBPß-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBPß knockout bone marrow cells survived longer than mice that received BCR-ABL-transduced wild-type (WT) bone marrow cells. Significantly higher levels of leukemic stem cells were maintained in BCR-ABL-transduced C/EBPß-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBPß is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBPß-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.