Signal transduction pathways that contribute to myeloid differentiation

Abstract

The production of mature, differentiated myeloid cells is regulated by the action of hematopoietic cytokines on progenitor cells in the bone marrow. Cytokines drive the process of myeloid differentiation by binding to specific cell-surface receptors in a stage-and lineage-specific manner. Following the binding of a cytokine to its cognate receptor, intracellular signal-transduction pathways become activated that facilitate the myeloid differentiation process. These intracellular signaling pathways may promote myelopoiesis by stimulating expansion of a progenitor pool, supporting cellular survival during the differentiation process, or by directly driving the phenotypic changes associated with differentiation. Ultimately, pathways that drive the differentiation process converge on myeloid transcription factors, including PU.1 and the C/EBP family, that are critical for differentiation to proceed. While much is known about the cytokines, cytokine receptors and transcription factors that regulate myeloid differentiation, less is known about the precise roles that specific signaling mediators play in promoting myeloid differentiation. Recently, however, the application of novel pharmacologic inhibitors, siRNA strategies, and transgenic and knockout models has begun to shed light on the involvement and function of signaling pathways in normal myeloid differentiation. This review will discuss the roles that key signaling pathways and mediators play in myeloid differentiation.

Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation

“…It has been well documented that MAPKs, especially MEK/ERK/MAP kinase signaling pathway, play an important role in myeloid differentiation (36,37). In line with these reports, vibsanin A induced the phosphorylation of Raf-1, MEK, and ERK in a dose-dependent manner, with marked increases in p38 and JNK phosphorylation (Fig.…”

“…In light of these observations, it was intriguing that c-Myc was rapidly downregulated at transcriptional and posttranscriptional levels by vibsanin A treatment, and the fact that block of the degradation of endogenous c-Myc and the enforced ectopic expression of c-Myc both effectively antagonized vibsanin Amediated differentiation strongly supported the role of decreased c-Myc in vibsanin A-induced AML cell differentiation. Our further investigations showed that repression of c-Myc was mediated by PKC-dependent activation of ERK/MAP kinase signaling pathway, which has been widely shown to mediate terminal differentiation in various lineages of hematopoietic cells (36,37). We conclude that vibsanin A induces AML cell differentiation by activating PKC, followed by ERK activation, which leads to c-Myc downregulation.…”

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

“…27,38 ERK signaling may have an important role in PMA-and ATRA-induced leukemia cell differentiation. [39][40][41] As reported by Lee's group, ERK2 activation is necessary for ATRA-induced differentiation. 39 Here, we also showed that the inhibition of ERK by U0126 could partially antagonize PMA and ATRA-induced differentiation of U937 cells (Supplementary Figure S10).…”

CD44-ligation induces, through ERK1/2 pathway, synthesis of cytokines TNF-α and IL-6 required for differentiation of THP-1 monoblastic leukemia cells

“…Interestingly, the mitogen-activated protein kinase (MAPK) family of serine/threonine kinases, which includes ERKs, JNKs (c-Jun N-terminal kinases) and p38MAPK, has an important role in the regulation of both monocytic differentiation, 5 and induction of cytokine synthesis by activated macrophages. 6 Accordingly, we asked whether MAPK has a role in CD44-induced monocytic differentiation and differentiating cytokine synthesis by THP-1 leukemic cells.…”