5,374 research outputs found
Inhibition of protooncogene expression by antisense oligodeoxynucleotides: biological and therapeutic implications.
No full textReview. No abstract available
Dissociation of c-fos induction from macrophage differentiation in human myeloid leukemic cell lines.
No full textTreatment of five human myeloid leukemic cell lines (KG1, ML3, HL-60, U-937, and HEL) with TPA was followed by macrophage differentiation and was accompanied by an early and transient increase in the mRNA level of c-fos proto-oncogene. The induction of c-fos was also observed in human cell lines K562 and K-Gla that did not respond to TPA with terminal macrophage differentiation. The treatment of HL-60 and U-937 cell lines with 1-oleoyl-2-acetylglycerol, a synthetic analog of diacylglycerol that, like TPA, stimulates protein kinase C activity, was followed by early and transient induction of c-fos mRNA in the absence of terminal macrophage differentiation. Finally, treatment of HL-60 with TPA in the presence of retinal, an inhibitor of protein kinase C, drastically reduced the induction of c-fos mRNA but had no effect on the terminal macrophage differentiation that is induced in this cell line by TPA. These results indicate that the induction of c-fos and terminal macrophage differentiation in response to TPA treatment can be dissociated in the in vitro models provided by human myeloid leukemic cell lines. Moreover, these findings suggest that the induction of c-fos is not only insufficient but may also be unnecessary for the differentiation along the monocyte-macrophage pathway
Ets-2 and c-Myb act independently in regulating expression of the hematopoietic stem cell antigen CD34.
Get PDFCD34 is currently the only well defined human hematopoietic stem cell marker and is expressed on 1-4% of normal bone marrow cells. Putative binding sites for Ets proteins, a family of transcription factors involved in the regulation of cell differentiation and proliferation in many cell systems, are present in the 5'-flanking region of the CD34 gene. Some of these sites are in close proximity to binding sequences of the encoded product of the proto-oncogene c-myb, which regulates CD34 expression by interacting with the Myb binding sites. Here we demonstrate that Ets-2 (i) transactivates the CD34 promoter in rodent fibroblasts upon interaction with Ets binding sites and (ii) induces expression of CD34 mRNA and protein in the CD34- human glioblastoma T98G cells. Ets-2 and c-Myb transactivate the CD34 promoter independently because specific transactivation is abrogated by site-specific mutations of the binding sites or by competition with oligomers that include wild type but not mutated Myb or Ets binding sites. Ets-2 and c-Myb appear to have addictive effects on transactivation of the CD34 promoter and on induction of CD34 mRNA. Instead, CD34 surface protein levels might be induced synergistically, raising the possibility of a posttranslational mechanism of CD34 expression in cells constitutively expressing c-Myb and Ets-2
Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors
No full textImatinib mesylate (IM) has become standard therapy for patients with chronic myeloid leukemia (CML), but CML stem cells are intrinsically resistant to IM and to second/third-generation tyrosine kinase inhibitors (TKIs), allowing the persistence of a 'reservoir' of BCR-ABL-expressing CML-initiating cells potentially responsible for disease progression. Although it is still controversial whether the 'insensitivity' of CML stem cells to treatment with TKIs is due to BCR-ABL-dependent or independent mechanisms, recent evidence indicates that treatment with IM suppresses BCR-ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Treatment of CML cells with IM/TKIs induces autophagy, a genetically regulated process of adaptation to metabolic stress which may allow tumor cells to become metabolically inert, enabling their survival under conditions that may mimic growth factor/nutrient deprivation. Based on this hypothesis, TKI-induced autophagy may 'antagonize' TKI-induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring 'sensitivity' of CML stem cells to treatment with IM/TKIs. Consistent with this, recent evidence indicates that phenotypically and functionally defined CML-enriched stem cells that are insensitive to treatment with TKIs are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may 'sensitize' CML stem cells to treatment with TKIs, thus preserving the high specificity of TKI-based therapies
Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins.
No full textShuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or be associated with the process of leukemogenesis. In BCR/ABL-expressing cells, there is a marked increase in the protein levels FUS, hnRNP A1 and hnRNP E2, three RNA-binding proteins involved in the regulation of mRNA processing, nucleocytoplasmic export, and translation. Ectopic expression and/or inhibition of the activity of these RNA-binding proteins affects proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important, but as yet unrecognized, role in BCR/ABL leukemogenesis. The identification of the mRNA subsets associated with RNA-binding proteins upregulated in BCR/ABL-expressing cells should functionally link the process of leukemogenesis with alteration of mRNA metabolism
The biology of CML blast crisis
No full textChronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (le, C/EBPalpha). Validation of the critical role of certain secondary changes (le, loss of p53 or C/EBPalpha function) in murine models of CMIL blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha)
Translational regulation by the p210 BCR/ABL oncoprotein
No full textThe ability of oncogenic proteins to regulate the rate of translation of specific mRNA subsets may be a rapid and efficient mechanism to modulate the levels and, in many cases, the activity of the corresponding proteins. In the past few years, we have identified several RNA binding proteins with translation regulatory activity whose expression is markedly activated in the blast crisis of chronic myelogenous leukemia, which represents the most malignant disease stage. Perturbation of the activity of some RNA binding proteins suppresses the leukemogenic potential of BCR/ABL-expressing cells. Most importantly, we have identified some of the targets of these RNA binding proteins. Two of these targets, c/ebp alpha and mdm2 mRNAs, are directly relevant for the altered differentiation and survival of leukemic cells. The identification of mRNA targets translationally regulated by RNA binding proteins overexpressed in tumor cells may lead to the development of therapeutic strategies aimed at modulating the translation rate of specific mRNAs
DNA binding and transactivation activity of A-myb, a c-myb-related gene.
No full textA partial-length A-myb complementary DNA recently cloned by low-stringency hybridization with a c-myb probe to complementary DNA libraries derived from human cell lines showed a high degree of homology with the DNA-binding domain of c-myb and B-myb, suggesting that A-myb also encoded a DNA-binding protein. We report here the sequence of the entire coding region of A-myb complementary DNA and show that the full-length GST-A-myb fusion protein or a truncated derivative corresponding only to the putative DNA-binding domain interacts specifically with Myb-binding sites of the c-myb responsive promoters, MIM-1 and CD34. In transient transfection assays, A-myb transactivated the bound promoters. These results suggest that, analogous to the other members of the Myb family, the A-myb gene encodes a bona fide transactivator. The distinct function of A-myb might derive from its pattern of expression and/or its relative potency as a transactivator of myb target genes
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