PubMed · 3467799
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R A Savage. 1987. Granulation in all blasts.. https://pubmed.ncbi.nlm.nih.gov/3467799/
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Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
To obtain comprehensive information about the genes involved in BCR/ABL-dependent leukemogenesis, samples from 15 chronic myelogenous leukemia (CML) patients and seven normal donors were analysed using a cDNA microarray assay. After subtraction of the artificial, random or cross-hybridization signals, data about 5315 genes have been effectively analysed in all samples. The assay revealed >/=4-fold difference in the average expression of 263 genes in all CML samples when compared to normal counterparts, with 148 genes being upregulated and 115 being downregulated. Differentially expressed genes include those associated with BCR/ABL-induced abnormalities in signal transduction, gene transactivation, cell cycle, apoptosis, adhesion, DNA repair, differentiation, metabolism and malignant progression. Interestingly, CML-blast crisis cells in peripheral blood differ from those from bone marrow, indicating major changes in gene expression profiles upon entering into the bloodstream. Moreover, BCR/ABL modulates expression of genes, which are involved in regulation of chromosome/chromatin/DNA dynamics during S and M cell cycle phase. Moreover, the ability of CML cells to recognize and respond to a pathogen infection may be compromised. Altogether, this work provides a large body of information regarding gene expression profiles associated with CML and also represents a source of potential targets for CML therapeutics.
Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusively in the transformation phase included amplification and/or translocation of bands 7p22-q22 and 19p13. These findings suggest that the loss of + 3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of SMZL. We hypothesize that the trisomy of 3q may correlate with the indolent nature of SMZL, and that the loss of this acquired abnormality leads to or accompanies the development of blastic tumors.