T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation.

T-cell prolymphocytic leukaemia (T-PLL) is a sporadic, mature T-cell disorder in which there is usually an aberrant T-cell receptor alpha (TCRA) rearrangement that activates the TCL1 or MTCP1-B1 oncogenes. As mutations of the Ataxia Telangiectasia (A-T) gene, ATM, are frequent in T-PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T-PLL. Using Southern blotting and the polymerase chain reaction, two of 60 TCRG coding joints were abnormal. In all cases, both TCRD alleles were deleted, IGH was germline, and patterns of TCRB and TCRA rearrangement were normal. However, in a case harbouring t(X;7)(q28;q35), we identified TCRB segment J beta 2.7 juxtaposed to MTCP1 exon 1. This is the first time that TCRB has been implicated in MTCP1 B1 activation. The structure of the breakpoint supports a model in which translocation activates a cryptic MTCP1 promoter. This analysis of V(D)J recombination is consistent with it being a variable that is independent of ATM in T-PLL.

Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: analysis by stage, immunophenotype, and morphology.

Fluorescence in situ hybridization (FISH) with a chromosome 12 specific alpha-centromeric probe was performed on interphase cells from 183 patients with B-cell chronic lymphocytic leukemia (CLL). Twenty one cases with trisomy 12 (11.5%) were detected. The number of trisomic cells ranged from 5.5% to 76% (mean 38.5%). No correlation was found between the presence of trisomy 12 and white blood cell count, hemoglobin level, platelet count, a specific immunophenotype, clinical stage, sex, splenomegaly, or lymphadenopathy. Morphologic review of all cases with trisomy 12 showed seven (33%) with more than 10% prolymphocytes and three (14%) with CLL of mixed cell type. While trisomy 12 is the most common chromosomal abnormality in CLL, it is more frequent in morphologically atypical cases, some of which may be undergoing transformation. There was a statistically significant difference in the incidence of atypical cases between those with (47%) and without (7.6%) trisomy 12 (P < .001). It remains to be determined whether this abnormality is associated with a worse prognosis; this is currently being investigated in the context of a national therapeutic trial. The technique used is more sensitive than conventional cytogenetic analysis, which in this series failed to detect trisomy 12 in six cases. FISH allows the systematic study on a large number of patients without the need of metaphase preparations.

Correlation between chromosomal abnormalities and blast phenotype in the blast crisis of Ph-positive CGL.

We carried out cytogenetic analysis in 23 patients with Ph-positive chronic granulocytic leukemia in blast crisis. In all cases the type of blast cell was characterized by cytochemistry, immunologic markers, and ultrastructural studies. Twelve cases were classified as myeloid transformation, six as lymphoid, two as mixed (lymphoid and myeloid), and two were unclassifiable. Duplication of Ph was the most frequent abnormality in the whole series. Trisomy 8, i(17q) and trisomy 19 were seen only in patients with myeloid blast crisis (53%, 30%, and 23%, respectively). Our findings suggest that the nature of additional chromosome abnormalities arising in blasts with features of myeloid differentiation are different from those in blasts showing lymphoid differentiation.

Chromosome and cell culture studies in eosinophilic leukaemia.

A cytogenetic analysis was carried out on bone marrow cells from 11 patients who presented with hypereosinophilia and the clinical features of the idiopathic hypereosinophilic syndrome. One of these patients was found to have trisomy 8 affecting the myeloid series, including eosinophils. In this patient, marrow eosinophils also showed asynchrony of nuclear-cytoplasmic maturation, and there were increased numbers of myeloid progenitor cells in the blood. Six months later, blast cell transformation occurred, and he died soon afterwards. These findings show that abnormalities in the karyotype of bone marrow cells and culture of blood progenitor cells may help to identity eosinophilic leukaemia among patients who present with features of the idiopathic hypereosinophilic syndrome.