Isoenzyme studies in human leukemia-lymphoma cell lines—V. Induction of differentiation by T-cell derived differentiation-inducing activity
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Bone marrow aspiration specimens of 5 different leukemia patients were electron microscopically observed. The results showed that the both as acute premyelocyte leukemia diagnosed cases (case 1 and 2) revealed many abnormal premyelocytes which contained cytoplasmic Auer bodies with markedly different structures. The case 3 and 4 were diagnosed as different types of hairy cell leukemia, namely typical hairy cell leukemia (type Ⅰ) and atypical hairy cell leukemia (type Ⅱ). The morphological difference of both type Ⅰ,Ⅱ cells were expressed mainly in the different lengths and numbers of the hairy processes on the cell surface and these differences can only be observed electron microscopically. The case 5 was a partly differentiated type of acute myelocytic leukemia and the cytoplasm of the premyelocyte contained only a few electron dense granules. The electron microscopy of these cells showed a marked superiority in its resolving power than the light microscopy and suggested its significance also in the diagnosis of leukemia.
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The chronic lymphocytic leukemia, the prolymphocytic leukemia and the hairy cell leukemia of B-cell immunophenotype are closely related disorders, but differ in their cytomorphological and clinical features. In an attempt to differentiate further among these forms of leukemia some immunological and cytochemical markers were studied. Simultaneously we measured adenosine deaminase and purine nucleosidephosphorylase activities by a method of paper radiochromatography in peripheral blood/bone marrow leukemic cells from 23 patients with chronic lymphocytic leukemia, 5 patients with prolymphocytic leukemia, one with prolymphocytoid transformation of chronic lymphocytic leukemia and 15 patients with hairy cell leukemia. The mosaic of immunological and cytochemical markers based on the sum of positive and negative features allowed for the correct diagnosis in a majority of cases. From the number of 43 investigated cases we found the typical enzyme patterns in 39 of them. On the basis of purine enzyme activity we were able to differentiate between chronic lymphocytic leukemia versus prolymphocytic and hairy cell leukemia. In one patient with chronic lymphocytic leukemia we could detect very early stage of prolymphocytoid transformation by increased activity of purine nucleosidephosphorylase activity. There were only two patients with chronic lymphocytic leukemia who were assigned to the prolymphocytic leukemia on the basis of purine nucleosidephosphorylase activity and two patients with hairy cell leukemia with atypical enzyme pattern attributable to the nonrepresentative number of pathological cells in the peripheral blood. Our study showed that purine nucleosidephosphorylase activity in leukemia cells may be useful as an additional parameter in the distinction of prolymphocytic from lymphocytic leukemia and that it may represent an enzymatic marker for early detection of prolymphocytoid transformation of chronic lymphocytic leukemia. Characteristic purine enzyme pattern was found also for diagnostic confirmation of hairy cell leukemia.
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Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. it's always classified as a sub-type of leukemia (CLL). Hairy cell leukemia makes up approximately 2% of all leukemias, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
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The transcription factor C/EBPβ controls differentiation, proliferation, and functionality of many cell types, including innate immune cells. A detailed molecular understanding of how C/EBPβ directs alternative cell fates remains largely elusive. A multitude of signal-dependent post-translational modifications (PTMs) differentially affect the protean C/EBPβ functions. In this study we apply an assay that converts primary mouse B lymphoid progenitors into myeloid cells in order to answer the question how C/EBPβ regulates (trans-) differentiation and determines myeloid cell fate. We found that structural alterations and various C/EBPβ PTMs determine the outcome of trans-differentiation of lymphoid into myeloid cells, including different types of monocytes/macrophages, dendritic cells, and granulocytes. The ability of C/EBPβ to recruit chromatin remodeling complexes is required for the granulocytic trans-differentiation outcome. These novel findings reveal that PTMs and structural plasticity of C/EBPβ are adaptable modular properties that integrate and rewire epigenetic functions to direct differentiation to diverse innate immune system cells, which are crucial for the organism survival.
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The enforced expression of c-myc is able to block the differentiation of myeloid cells. More recently, it has been shown that the correct functioning of c-Myc is not only dependent on the abundance of its dimerization partner, Max, but also on the levels of two other proteins which complex with Max, Mad and Mxil. Analysis was made of the levels of their mRNAs, relative to those of c-myc mRNA, during the induced differentiation of myeloid leukaemic HL60 and U937 cells. This revealed that, the abundance of mxil and max mRNA were largely maintained at levels comparable to those observed in untreated cells, but the levels of max mRNA were found to be markedly reduced at the very late stages of differentiation in HL60 cells induced by TPA. In contrast, the levels of mad mRNA were rapidly increased following differentiation induction by TPA. However, it was found that differentiation to granulocytes or monocytes/macrophages could also be achieved without a concomitant increase in the abundance of mad mRNA. To further investigate the role of Mad during the differentiation of myeloid cells E-box DNA-binding was analysed. While Myc:Max complexes were lost rapidly following differentiation induction, no Mad-containing complexes were detected during differentiation to monocytes/macrophages, and those which were detected during granulocytic differentiation were only evident at the very late stages. The subsequent analysis of these Mad-containing complexes revealed that they were also unlikely to be able to antagonise c-Myc function as they did not contain Max. In light of these findings, it was decided not to study these factors further, but to focus on the role played by c-myc in the control of differentiation per se. Although the mechanism by which c-Myc affects this process remains unknown, it is considered that it might result indirectly as an outcome of the continued cell-cycle progression invoked by c-Myc in cells which must growth arrest in order to differentiate. However, it is equally possible that a differentiation blockage occurs through a mechanism independent of c-Myc's involvement in cell-cycle progression. An analysis was therefore made of a differentiation-defective variant of the U937 cell line which, following treatment with TPA, does not differentiate, but rapidly ceases to proliferate, arresting at the G0/G1 phase of the cell cycle. Analysis during growth arrest revealed that, although this line down-regulated the expression of the Myc target gene, ornithine decarboxylase, it continued to express high levels of c-Myc protein, which retained the ability to bind its target sequence, CACGTG. Consequently, it was hypothesised that the continued expression of c-Myc in these cells may be responsible for their inability to differentiate in response to treatment with TPA. In agreement with this, down-regulation of the levels of c-Myc by antisense oligonucleotides directed against c-myc mRNA resulted in these cells acquiring characteristics of a terminally differentiated cell. As Mad, Max and Mxil have all been shown to antagonize c-Myc function, an analysis was also made for mutations in the genes for these proteins. Both HL60 and HeLa cells were found to be hemizygous for max. Sequencing of the remaining allele in these cell lines revealed three nucleotide changes, when compared to the published sequence. However, these changes did not result in any amino acid change. The relevance of all these findings to the regulation of myeloid differentiation, and in particular to the involvement of c-Myc in these processes, is discussed.
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