ISSN:0021-9541    

DOI:10.1002/jcp.1041210403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractHemopoietic stem cells may give rise to progeny like themselves or undergo determination; this event is followed by a series of maturation divisions ending in proliferatively inert but functional cells. In normal hemopoiesis and acute leukemia stem cell renewal is not exact; proliferative capacity is lost gradually. As a consequence, clonal populations cannot be continued indefinitely. Postdeterministic differentiation normally leads to cellular diversity; following transformation this diversity is increased, with the production of blast cells together with one or more myelopoietic lineage. The blasts are heterogeneous both in their proliferative capacity and their phenotypes, as determined using immunologically defined markers. Both self‐renewal and determination are considered to be irreversible in vivo. By contrast, in continuous myelopoietic cell lines self‐renewal is sufficiently precise to confer immortality on the populations. Furthermore, both determination and renewal may in some instances be reversible. The differences between normal or leukemic hemopoiesis in vivo and continuous lines in culture limits the value of the latter for studies of normal blood formation or the clonal hemopath

ISSN:0021-9541    

DOI:10.1002/jcp.1041210404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0021-9541    

DOI:10.1002/jcp.1041210405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractA nonfunctional immunoglobulink‐chain gene previously shown to contain intracisternal A‐particle (IAP) sequences within one of its introns was further characterized by DNA and RNA blot analysis. The results of these experiments indicate that the joining of the IAP sequences to thek‐chain gene was a consequence of an insertion event which presumably involved a complete IAP gene. It is postulated that the insertion of the IAP gene has altered the secondary or tertiary structure of thek‐chain pre‐mRNA, resulting in the utilization of a “cryptic” 5′ splice site. The detection of numerous IAPs in isogenous wild‐type hybridoma cells by electron microscopy suggests that transposition of IAP genes might proceed via the reverse transcription of IAP‐associated RNA. These findings raise the possibility that transposition of IAP genes might also occur in other IAP‐positive mouse cells. In particular, insertional mutagenesis by IAP genes in IAP‐producing tumor cells could play a role in tumor cell heterogeneity or tumor progression. We have also investigated the possibility that IAP‐related sequences might be present in the human genome. Using nonstringent hybridization conditions, multiple discrete restriction fragments could be detected in human DNA with several

ISSN:0021-9541    

DOI:10.1002/jcp.1041210406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0021-9541    

DOI:10.1002/jcp.1041210407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0021-9541    

DOI:10.1002/jcp.1041210408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0021-9541    

DOI:10.1002/jcp.1041210409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0021-9541    

DOI:10.1002/jcp.1041210410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractTreatment of a variety of highly tumorigenic mouse lines in vitro with chemical mutagens, such as ethyl methane sulfonate (EMS) or N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG), can result in extraordinarily high frequencies (sometimes in excess of 90%) of strongly immunogenic clones unable to grow progressively in normal syngeneic hosts. These clones will, however, grow in immunosuppressed hosts and gradually regain tumorigenic ability in normal mice if maintained in long‐term (several months—1 year) culture, i.e., they are often phenotypically unstable. These features—phenotypic drift and high frequency—make it unlikely that point mutations are the underlying mechanism involved in the generation of the variants. Results presented here demonstrate that these observations can be reproduced on the same tumor lines using 5‐azacytidine—an analogue of cytidine which can be incorporated into DNA causing subsequent extensive hypomethylation of cytosine residues in the absence of any significant mutagenic effects. Furthermore, 5‐azacytidine treatment of a nonmetastatic mouse mammary tumor led to the emergence of a small number of heritable but unstable tumor clones capable of spontaneous metastatic spread. Because it is known that DNA hypomethylation can lead to transcriptional activation of normally silent genes, that altered methylation patterns can be somatically replicated with a high but not perfect fidelity, and that mutagens can cause DNA hypomethylation, we propose that DNA hypomethylation followed by de novo methylation represents a plausible mechanism to account not only for the induction of the nontumorigenic variants but for a number of aspects of tumor progression and tumor heterogeneity, as well. In particular, we refer to heritable phenotypic alterations in tumor cell populations which occur at very high frequency but which are not necessarily stable over

ISSN:0021-9541    

DOI:10.1002/jcp.1041210411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractParallel clonal populations grown to small defined sizes were used to quantitate rates of generation of metastatic cells. In murine KHT fibrosarcoma and B16 melanoma lines, metastatic cells are generated at effective rates of 10−5per cell per generation, or greater. These variant cells are unstable, and are apparently lost at very high rates. It thus appears that metastases could arise from unstable variants, and that rapid rates of change in some phenotypes may be an important feature of malignant progression. We have called such rapid variationsdynamic heterogeneity.This may be a useful concept for further investigating aspects of tumor heterogeneit

ISSN:0021-9541    

DOI:10.1002/jcp.1041210412

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY