Lethal Giant Larvae 1 Tumour Suppressor Activity Is Not Conserved in Models of Mammalian T and B Cell Leukaemia

In epithelial and stem cells, lethal giant larvae (Lgl) is a potent tumour suppressor, a regulator of Notch signalling, and a mediator of cell fate via asymmetric cell division. Recent evidence suggests that the function of Lgl is conserved in mammalian haematopoietic stem cells and implies a contribution to haematological malignancies. To date, direct measurement of the effect of Lgl expression on malignancies of the haematopoietic lineage has not been tested. In Lgl1^−/− mice, we analysed the development of haematopoietic malignancies either alone, or in the presence of common oncogenic lesions. We show that in the absence of Lgl1, production of mature white blood cell lineages and long-term survival of mice are not affected. Additionally, loss of Lgl1 does not alter leukaemia driven by constitutive Notch, c-Myc or Jak2 signalling. These results suggest that the role of Lgl1 in the haematopoietic lineage might be restricted to specific co-operating mutations and a limited number of cellular contexts.     

Meningeal Carcinomatosis

Meningeal carcinomatosis without gross tumour in the substance of the brain or spinal cord has been reported rarely. Two cases observed at the Victoria General Hospital, Halifax, presented a bizarre clinical picture consisting of signs of meningeal irritation without fever, and psychotic behaviour. Examination of the cerebrospinal fluid revealed low sugar concentration and increased pressure, protein and cells. In one case these cells were readily identified as malignant on stained smears. At autopsy the surfaces of the cerebral hemispheres, cerebellum and brain stem were covered by an opalescent film and on section the subarachnoid space was densely packed with malignant cells. Both primary tumours were adenocarcinomas, one originating in the gallbladder and one in the rectum. The diagnosis of meningeal carcinomatosis must be considered in patients presenting with profound mental changes and meningeal irritation without fever. Diagnosis may be confirmed by cytological examination of the cerebrospinal fluid. The primary tumour is most commonly an adenocarcinoma. There is no satisfactory treatment available.     

Acyl chain selection couples the consumption and synthesis of phosphoinositides

Phosphoinositides (PIPn) in mammalian tissues are enriched in the stearoyl/arachidonoyl acyl chain species (“C38:4”), but its functional significance is unclear. We have used metabolic tracers (isotopologues of inositol, glucose and water) to study PIPn synthesis in cell lines in which this enrichment is preserved to differing relative extents. We show that PIs synthesised from glucose are initially enriched in shorter/more saturated acyl chains, but then rapidly remodelled towards the C38:4 species. PIs are also synthesised by a distinct ‘re‐cycling pathway’, which utilises existing precursors and exhibits substantial selectivity for the synthesis of C38:4‐PA and ‐PI. This re‐cycling pathway is rapidly stimulated during receptor activation of phospholipase‐C, both allowing the retention of the C38:4 backbone and the close coupling of PIPn consumption to its resynthesis, thus maintaining pool sizes. These results suggest that one property of the specific acyl chain composition of PIPn is that of a molecular code, to facilitate ‘metabolic channelling’ from PIP2 to PI via pools of intermediates (DG, PA and CDP‐DG) common to other lipid metabolic pathways.