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

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 beta (C/EBP beta), a regulator for 'emergency granulopoiesis,' in the pathogenesis of CP-CML was examined. C/EBP beta 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/EBP beta, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBP beta-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBP beta 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/EBP beta-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBP beta is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBP beta-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells. Leukemia (2013) 27, 619-628; doi:10.1038/leu.2012.258