c-kit is a tyrosine kinase receptor whose ligand is stem cell factor (SCF). Gene alteration of the c-kit extracellular domain was analysed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in 25 patients with myeloproliferative disorders (MPD). In the N-terminal part of the domain, mobility shifts indicating sequence alteration were detected in three of the patients, two primary myelofibrosis (PMF) and one chronic myelogenous leukaemia (CML). The subsequent sequencing revealed the same point mutations at codon 52 causing amino acid substitution (Asp-->Asn). To our knowledge this is the first report with a c-kit point mutation found in human fresh tumour cells.

Myeloproliferative disorders (MPD) constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Myeloid stem cells and/or progenitor cells from MPD have been considered sensitive to hematopoietic growth factors, including erythropoietin, thrombopoietin and stem cell factor (SCF). SCF is a ligand for c-kit receptor with tyrosine kinase. We analysed the gene alteration of the c-kit extracellular domain in MPD patients by PCR-SSCP and subsequent nucleotide sequencing. The point mutation in the N-terminal part of the domain, codon 52 (Asp-->Asn), was found in two patients with primary myelofibrosis and one with chronic myelogenous leukemia. We review the literature regarding the role of SCF/c-kit system in the oncogenesis of leukemia and MPD, and then discuss the significance of our finding in the context of growth advantage of the mutated clones over the normal clones.

Myelofibrosis is sometimes associated with accelerated and blastic phase of chronic myelogenous leukaemia (CML). In order to investigate the role of platelet derived growth factor (PDGF) in this pathogenesis, expression and production of PDGF was studied in the blast cells from 11 patients. Five patients had myelofibrosis with myeloid blasts, while six patients did not show fibrosis, including three with myeloid blasts and three with lymphoid blasts. PDGF-A chain transcript was expressed in most of the patients. On the other hand, PDGF-B chain transcript was detected in all of the five patients with myeloid blasts and with fibrosis, in one of the three patients with myeloid blasts and without fibrosis, and in none of the three lymphoid crisis patients without fibrosis. In the patients with myeloid blasts and with fibrosis, PDGF protein, PDGF-AB and/or PDGF-BB, was found to be secreted from blast cells. In addition, the PDGF activity in the culture of myeloid blasts from two patients with fibrosis was also growth stimulatory for human marrow fibroblasts. These results suggest that expression and secretion of PDGF-AB or PDGF-BB in blast cells play an important role in the pathogenesis of marrow fibrosis associated with accelerated and blastic phase of CML.

B-cell chronic lymphocytic leukemia (B-CLL) associated with bone marrow fibrosis is described. The conditioned medium of the CLL cells contained a high quantity of interleukin 1 alpha (IL-1 alpha), and showed growth promoting activity for marrow fibroblasts which was partially inhibited by anti IL-1 alpha antibody. In addition, the conditioned medium as well as IL-1 alpha stimulated the growth of marrow fibroblasts from the patient. These results strongly suggested the marrow fibrosis occurred by the secretion of IL-1 alpha from the CLL cells and its growth stimulation of marrow fibroblasts. As far as we know, this is the first case in which B-CLL was associated with marrow fibrosis, and its mechanism was investigated.

This study aimed to examine the sleep architecture and craniofacial morphology in a group of children divided by different levels of apnoea-hypopnoea index (AHI), 5, 4.5, 4, 3.5, 3 and 2.5, and to determine an AHI threshold value at which sleep architecture is most affected. 23 children, who were selected from a preliminary questionnaire survey about sleep-related breathing disorders, were evaluated with cephalometric radiographs and overnight polysomnography. The findings indicated that the children with AH1 > or = 2.5 and > or = 3 showed significantly larger numbers of waking (p < 0.005) and desaturation index (p < 0.01) than those with AHI <2.3 and <3, respectively. Significantly (p < 0.05) higher amounts of waking and lower amounts of REM as a percentage of total sleep time (TST) were also found in the children with AH1 > or = 3. In the subgroups with AHI > or = 3.5 and > or = 4, only the percentage of REM was found to be significantly (p < 0.05) lower. No significant differences were found at the AHI threshold of 4.5 and 4. AHI correlated significantly (p < 0.05) with the number of awakenings, amount of waking as a percentage of TST, desaturation index and oxygen saturation nadir. Higher incidence of skeletal Class II pattern was found in children with AHI > or = 2.5 and > or = 3, and Class III in those with AHI <2.3 and <3, respectively. The effects on polysomnographic characteristics demonstrated to be the greatest on children at the AHI threshold of 3. In addition, the evaluation of oxygen saturation can be used to provide some information concerning the severity of sleep-related breathing disorders.