Transcriptional and post-transcriptional regulation of IL-1 beta, IL-6 and TNF-alpha genes in chronic lymphocytic leukaemia.

The present study was designed to define the mechanisms of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha) gene regulation in chronic lymphocytic leukaemia of B cell origin (B-CLL). By nuclear run-on analysis, all B-CLL cases displayed high levels of nuclear transcription of the IL-6 and TNF-alpha genes, whereas IL-1 beta gene transcription was only barely detectable. Upon in vitro culture for 1 h, B-CLL cells from different patients were substantially heterogeneous in terms of expression of steady state mRNA levels of IL-1 beta, IL-6 and TNF-alpha even though the pattern of nuclear transcription of these cytokines was only marginally affected by in vitro culture. mRNA stability was then examined and cytokine gene transcripts showed a half life of more than 2 h in cultured B-CLL cells and treatment with cycloheximide (CHX) did not affect cytokine transcript levels in B-CLL cells. These results indicate that: steady state levels of each mRNA do not reflect the rate of nuclear transcription of these cytokines in fresh or cultured B-CLL cells, that purification and in vitro culture of leukaemic cells may amplify cytokine gene expression in B-CLL, and that cytokine gene transcripts are relatively stable in B-CLL.

Acute undifferentiated leukemia with CD7+ and CD13+ immunophenotype. Lack of molecular lineage commitment and association with poor prognostic features.

The authors studied six adult patients with acute leukemia with these unusual characteristics: unclassifiable morphology and undifferentiated cytochemistry by French-American-British (FAB) criteria; concurrent expression of CD13 (and CD33) myeloid and early T-cell CD7 immune markers; no evidence of T-cell lineage commitment as determined by T-cell receptor beta (beta), gamma (gamma), and delta (delta) chain gene rearrangement study and cytoplasmic CD3 epsilon expression; and no evidence of myeloid cell lineage commitment, as shown by absent myeloid-specific c-fms proto-oncogene expression and negative myeloperoxidase ultrastructural staining (one case). Clinically, these diagnostic features matched with a poor prognosis, being associated with refractoriness to treatment, relapse and progression of disease, antecedent hematologic abnormality, and other malignancy. These cases may represent a distinct stem cell leukemia syndrome deserving immediate recognition and a nonconventional chemotherapeutic approach.

Expression of leukocyte alkaline phosphatase gene in normal and leukemic cells: regulation of the transcript by granulocyte colony-stimulating factor.

The levels of leukocyte alkaline phosphatase (LAP) messenger RNA (mRNA) are evaluated in B and T lymphocytes, monocytes, and polymorphonuclear cells (PMNs), and this transcript is found to be present only in PMNs. Precursors of the myelomonocytic pathway, represented by leukemic cells isolated from several cases of chronic myelogenous leukemia (CML) in its stable and blastic phase and acute myelogenous leukemia (AML), are devoid of LAP transcript. These data support the notion that LAP is a marker of the granulocyte terminal differentiation. Despite the absence of LAP mRNA in both the myeloid and the lymphoid precursors, nuclear run-on experiments show constitutive transcription of the LAP gene in leukemic cells obtained from AML, CML, as well as acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia (B-CLL). In CML and in chronic myelo-monocytic leukemia (CMML) PMNs, granulocyte colony-stimulating factor (G-CSF) specifically accumulates LAP mRNA without showing a substantial increase in the rate of transcription of the LAP gene. Once increased by G-CSF, LAP mRNA is very stable, showing a half-life of more than 4 hours in the presence of actinomycin-D. G-CSF is suggested to play a pivotal role in the modulation of LAP transcript in PMNs.