Differentiation induction in acute promyelocytic leukemia

Abstract

Hematopoiesis or blood cell formation is a continuous process in which maturing hematopoietic cells with a limited life span are formed. The formation of all different blood cell lineages originates from a small population of pluripotent stem cells that reside in the bone marrow. Progenitor cells that are committed to a certain lineage of differentiation orginate from these pluripotent stem cells. Hematopoiesis is regulated by a network of cytokines and hematopoietic growth factors (HGF). The HGFs are produced locally by stromal cells. mature blood cells, endothelial cells or specialized cells in organs such as lungs, liver and kidney. The levels of HGFs are elevated in response to extracellular stimuli, such as infection or bleeding, when a rapid rise of specific blood cell types is necessary. HGFs exert their effect by binding to their corresponding receptors expressed on the membrane of their target cells. Ligand binding results in the activation of downstream signaling pathways. A cascade of phosphorylation events is involved in signal transduction. In one pathway, the JAK Uanus kinase) family of protein tyrosine kinases are tyrosine phosphorylated and in turn activate a family of latent cytoplasmic transcription factors, called STAT (Signal Transduction and Activation of Transcription) proteins. Following their activation, these STAT proteins are assembled into complexes which then translocate to the nucleus and activate target genes by interaction with specific DNA sequences. Another major HGF receptor signal transduction pathway includes proteins that belong to the Ras family. Signaling molecules like Shc and Grb2 function as adaptor proteins in this pathway by linking phosphorylated receptors to downstream effectors. Grb2 binds to the activated receptor, and to Sos (Son of sevenless) which after translocation to the plasma membrane activates Ras triggering phosphorylation of Rat. The products of Raf, a serine tyrosine kinase and mitogen activated protein kinases (MAPK) transmit signals for futher transmission to the nucleus. In the nucleus, activation of transcription factors by phosphorylation or other mechanisms results in activation of genes involved in cellular proliferation and differentiation. Apart from affecting transcription, activated Ras results in cyclin D1 activation and stimulates p27kip1 degradation via Rho. Both events positively infiuence cell cycle entry (Figure 1.2)