The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron.

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed.

We have compared the levels of inositol metabolites in three pairs of normal and transformed cells which have been matched with respect to their cell lineage, differentiation and proliferation status: (i) normal human myeloid blast cells and the human promyelocytic leukaemic cell line, HL60; (ii) human umbilical-cord T-helper cells and C8166 cells, a HTLV-1-transformed T-helper cell line; and (iii) an interleukin 3-dependent long-term culture of murine pro-B-cells (BAF3) and BAF3 cells transformed by transfection with the bcr-abl oncogene. Complex patterns of inositol metabolites were present in each of the cell populations. Although there were a number of differences in the levels of certain inositol metabolites between individual cell populations in the paired groups, we did not observe any consistent difference in the levels of inositol metabolites between the proliferating normal and transformed cells. In particular, our data do not support the reported correlation between elevated glycerophosphoinositol (GroPIns) levels and transformation of cells by membrane and cytoplasmic oncogenes which has been reported by other workers. All the cells contained high concentrations of Ins(1,3,4,5,6)P5 (between 12 and 55 microM) and InsP6 (between 37 and 105 microM). The HTLV1-transformed T-helper cells had particularly high levels of total inositol phosphates (predominantly GroPIns, an unidentified inositol bisphosphate and InsP6). The observations are discussed with reference to cell transformation and to the differentiation status of the paired populations.

HL60 cells were adapted to grow in a serum-free medium containing 1 mg l$^{-1}$ inositol, in which they differentiated normally towards neutrophils (in 0.9% by volume dimethylsulphoxide) and towards monocytes (in 10 nM phorbol myristate acetate). Cells that had been equilibrium-labelled with [2-$^{3}$H]myo-inositol contained a complex pattern of inositol metabolites, several of which were at relatively high concentrations. These included InsP$_{5}$ and InsP$_{6}$, which were present at concentrations of about 25 $\mu $M and 60 $\mu $M, respectively. Striking and different changes occurred in the levels of some of the inositol polyphosphates as the cells differentiated towards either neutrophils or monocytes. Most notable were a large but gradual accumulation of Ins(1,3,4,5,6)P$_{5}$ as HL60 cells decreased in size and acquired neutrophil characteristics, and much more rapid and sequential declines in InsP$_{4}$, InsP$_{5}$ and InsP$_{6}$ as the cells started to take on monocyte character. There was a marked accumulation of free inositol and of phosphatidylinositol in the cells during neutrophil differentiation, probably caused at least in part by an increased rate of inositol uptake providing an increased intracellular inositol supply. The same accumulation of Ins(1,3,4,5,6)P$_{5}$ occurred during neutrophil differentiation, whether it was induced by dimethylsulphoxide or by a combination of retinoic acid and a T-lymphocyte cell line-derived differentiation factor. Ins(1,4,5)P$_{3}$, a physiological intracellular mediator of Ca$^{2+}$ release from membrane stores, did not change in concentration during these differentiation processes. These observations suggest that some of the more abundant cellular inositol polyphosphates play some important, but not yet understood, role either in the processes of haemopoietic differentiation or in the expression of differentiated cell character in myeloid cells.