CCAAT/Enhancer Binding Protein α Is a Regulatory Switch Sufficient for Induction of Granulocytic Development from Bipotential Myeloid Progenitors

Abstract

The transcription factor CCAAT/enhancer binding protein ␣ (C/EBP␣) regulates a number of myeloid cell-specific genes. To delineate the role of C/EBP␣ in human granulopoiesis, we studied its expression and function in human primary cells and bipotential (granulocytic/monocytic) myeloid cell lines. We show that the expression of C/EBP␣ initiates with the commitment of multipotential precursors to the myeloid lineage, is specifically upregulated during granulocytic differentiation, and is rapidly downregulated during the alternative monocytic pathway. Conditional expression of C/EBP␣ alone in stably transfected bipotential cells triggers neutrophilic differentiation, concomitant with upregulation of the granulocyte-specific granulocyte colonystimulating factor receptor and secondary granule protein genes. Moreover, induced expression of C/EBP␣ in bipotential precursors blocks their monocytic differentiation program. These results indicate that C/EBP␣ serves as a myeloid differentiation switch acting on bipotential precursors and directing them to mature to granulocytes.

Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

“…Instead we found a significant increase of neutrophils in Trib1 KO liver. As Trib1 is a negative regulator of C/EBPα and C/EBPα is required for neutrophil differentiation from myeloid progenitors, the increase of neutrophils in Trib1 KO mice was likely due to a consequence of up‐regulation of C/EBPα, consistent with reports showing that overexpression of C/EBPα increased the neutrophil population 11. There was no statistically significant difference in expression of neutrophil cytokines in Trib1 KO liver (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1178/full), suggesting that accumulation of neutrophils in the liver was due to increased neutrophil production rather than increased neutrophil chemoattractants in the liver.…”

“…C/EBPα is specifically up‐regulated during granulocytic differentiation and is rapidly down‐regulated during the alternative monocytic pathway. Conditional expression of C/EBPα alone in stably transfected bipotential myeloid cells triggers neutrophilic differentiation 11. Thus, Trib1 deficiency may exhibit a phenotype similar to overexpression of C/EBPα.…”

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

“…Indeed, activation of C/EBa in K562 cells induced a decrease in the expression of STAT 5 and Mcl-1, which was blocked in Gfi-1-silenced C/EBPa-ER-K562 cells (Supplementary Figure 4). The decrease in expression/activity of STAT 5 and Mcl-1 may be important not only for the ability of different levels of C/EBPa expression to influence self-renewal and commitment to granulocyte/monocyte progenitors of normal hematopoietic stem/ progenitor cells, 5,7 but also for the consequences on the proliferation and survival of myeloid leukemia cells.…”

“…C/EBPa exemplifies a transcription factor with distinct roles in normal and leukemic cells because it regulates the balance between differentiation and proliferation in the early stages of normal myelopoiesis 5,7 but is functionally or genetically inactivated in many types of myeloid leukemia in which the homeostatic coordination between proliferation and differentiation is lost. 8,9 Moreover, when ectopically expressed it induces differentiation and inhibits proliferation of myeloid leukemia lines and primary cells from patients with chronic myelogenous leukemia (CML)-blast crisis.…”

BCR/ABL, mRNA translation and apoptosis

“…This is, indeed, the case of the hnRNP E2-dependent regulation of c/ebpa mRNA translation. 85 C/EBPa, whose expression is essential for granulocytic differentiation of multipotent progenitor cells, 126,127 is downmodulated in established BCR/ABL-expressing 32Dcl3 lines, in Ph 1 myeloid CML blast crisis cell lines and in primary bone marrow cells from CML blast crisis patients. 85 The downregulation of C/EBPa expression correlates with the levels of BCR/ABL, suggesting that the effects are dose-dependent.…”