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RADIATION LEUKO.pptx

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RADIATION LEUKO.pptx

  1. 1.  Studies have often demonstrated that these tumour- specific alterations are associated with activation of cellular proto-oncogenes or the inactivation of tumour suppressor genes.  Ionizing radiation induces a broad range of neoplasms in both man and experimental animals. Point mutations and chromosome translocations that activate proto-oncogenes and deletions that lead to a loss of function of tumour suppressor genes all probably play a role in the initiation (and progression) of these diseases.  The DNA of a cell is damaged by ionizing radiation that may principally, but not exclusively, initiate oncogenesis through mechanisms involving deletion ,rearrangement of segments of DNA or both.
  2. 2.  The activation of proto-oncogenes seems to occur through two mechanisms. For example, in proto- oncogenes such as RAS, the DNA base pair (bp) changes needed for activation are limited thus providing a small molecular target of may be only a few base pairs.  For the gene-specific translocations involving juxtaposition of proto-oncogenes such as ABL or BSL-2 with other genes, the target would be larger (maybe up to 10' bp) although it could, in principle, be necessary to damage the DNA at two specific sites rather than one.
  3. 3.  However, with the loss-of-function mutations characteristic of tumour suppressor genes, such as Rb, APC or p53, the situation is different.  Inactivation may occur through point mutation, small deletions within the gene or larger deletions involving whole chromosome segments (about 107 bp), the principal limit to the size of such DNA deletions being the extent to which the cell can sustain viability following large losses of genetic material.  Thus, on simple biophysical arguments it would seem that radiation induced loss-of-function mutations, since they appear to offer the larger target size by perhaps two or three orders of magnitude, may dominate the spectrum of initiating events for radiation-induced carcinogenesis
  4. 4.  Support for this concept comes from molecular studies with radiation-induced mutations where the main mechanism has been shown to be through gross genetic change - usually DNA deletions. Although such studies in no way exclude radiation mutagenesis through point mutation, they indicate ionizing radiation to be a rather weak point mutagen
  5. 5.  Many chemical agents also induce gross chromosomal damage, but the mechanisms are fundamentally different from those of radiation as the majority of chemicals principally act to produce point mutations.  Thus, the major mechanistic difference at the cellular level between radiation-induced and chemical-induced oncogenesis is probably related to their relative efficiencies at inducing point mutations or activation of proto- oncogenes, and some variations in the spectrum of neoplasms induced by radiation and chemical carcinogens are, therefore, possible.  Moreover, it is feasible that specific point mutations in tumour genes may serve as a signature of prior exposure to chemical carcinogens
  6. 6.  The commonest and most extensively characterized genetic abnormalities that are associated with leukaemia are the chromosomal translocations that give rise to fusion genes encoding oncogenic proteins. The classical example, found in CML, gives rise to the Philadelphia (Ph) chromosome which involves a translocation between chromosomes 9 and 22 and results in the juxtaposition of the BCR gene and the ABL proto-oncogene  several other types of chromosomal aberrations exist and their fusion genes have been identified in acute leukaemia. These include the DEK-CAN (chromosomes 6 and 9) and AML1-ETO (chromosomes 8 and 21) genes in AML, and the TEL AML1 (chromosomes 12 and 21) and MLL-AF1P genes (chromosomes 1 and 11) in ALL. Also trisomy and polysomy of chromosome 21 are frequent anomalies in ALL
  7. 7.  High doses of ionizing radiation are capable of generating such fusion genes in haemopoetic cell lines in vitro. The genes are generally induced at different frequencies - AML1-ETO having the highest frequency and differ for the different cell lines
  8. 8.  Typically in these secondary leukaemias, loss of part or all of chromosomes 5 and/or 7 is observed with the frequency of abnormalities of both chromosomes being more prevalent in patients who receive both types of therapy.  In the case of secondary AML following treatment with chemotherapeutic drugs, there are some significant genotypic and phenotypic differences between, for example, AML associated with alkylating agents and the epipodophyllotoxins.  While non-balanced abnormalities of chromosomes 5 and 7 are again the most frequently observed in neoplastic processes arising after alkylating agent therapy, leukaemias occurring after treatment that includes epipodophyllotoxins often feature balanced chromosomal translocations. These latter leukaemias often have a latency period of about 2 years compared with typically 6 years following treatment with alkylating agents.
  9. 9.  Chromosome rearrangements and deletions are major features of the oncogenic process and there is an ongoing debate about the significance of specific sites of instability- the so-called fragile sites.  Some fragile sites are believed to be preferential targets for the clastogenic action of DNA-damaging agents such as ionizing radiation, although no overall association between common fragile sites and cancer-associated breakpoints has yet been shown-except possibly with respect to certain leukaemias.  The molecular structures of fragile sites are not known, but it seems likely that they contain certain repeat DNA sequences in particular telomere-like repeat (TLR) sequences which may recombine at high frequency.
  10. 10. THANK YOU

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