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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.

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1a,25 Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) in regulating the growth and di erentiation of the normal prostate gland yet prostate cancer cells appear signi®cantly less sensitive to this action. Vitamin D 3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative e ects of 1a,25(OH) 2 D 3 and therefore it is unclear why prostate cancer cell lines are signi®cantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1a,25(OH) 2 D 3 are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 mM and 15 nM respectively), which alone were relatively inactive, synergized with 1a,25(OH) 2 D 3 in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D 3 hexa¯uoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclindependent kinase inhibitor, p21 (waf1/cip1) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1a,25(OH) 2 D 3 during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D 3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgendependent and independent prostate cancer. Oncogene (2001) 20, 1860 ± 1872.