BIOLOGY 2F03 Chapter Notes - Chapter 7-8: Tumor Suppressor Gene, Fanconi Anemia, Leukemia
20 May 2018
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ONCOGENES AND TUMOUR SUPPRESSOR GENES IN ACUTE LEUKAEMIA; M2 & M3 AML
1. It is thought that most cases of leukaemia are caused by the 2 hit hypothesis of genetic mutation
• Acute leukaemias are clonal expansions of abnormal cells, commonly as a result of a somatic
mutation in a proto-oncogene, resulting in oncogenesis
o Mutations in oncogenes often affect transcription factors
• Mutations in acute leukaemia often demonstrate the dominant negative effect
o The mutant inhibits the gene-product of the normally functioning allele, as well as making a
dysfunctional gene product itself
• One mutation is rarely enough – you need one affecting survival and one affecting differentiation
• ALL follows the 2 hit hypothesis
o You get one mutation in utero (eg t12;21)
o Another mutation after birth triggers ALL
2. The nature of mutations in oncogenesis (5)
• Point mutations
• Interstitial deletions, bringing proto-oncogenes into contact with the wrong gene promoters
• Internal tandem duplication (MLL, FLT3)
• Amplification of an oncogene (rare)
• Translocations, which, again, bring a proto-oncogene into contact with a wrong promoter
• Insertional oncogenesis occurs after gene therapy, where the gene is inserted into the wrong place
Inherited genetic abnormalities in oncogenesis can be the first hit
• Haploinsufficiency (loss of 1 allele) of a gene that is critical for normal differentiation
o Eg loss of 1 copy of RUNX1 in familial thrombocytopenia can predispose to AML
• Loss of function of tumour suppressor genes
o Neuroblastomas (NF1), retinoblastomas (RB1)
• Chromosomal fragility syndromes increase likelihood of somatic mutations occurring
o Fanconi anaemia
• Abnormalities of genes that repair DNA mean that random errors are not corrected
• Abnormalities of genes that degrade mutagens can lead to environmental mutagenesis
3. Abnormalities in tumour suppressor genes can cause a variety of leukaemias
• Whole/partial chromosome deletion as well as small mutations can affect normal tumour
suppressor function
• Tumour suppressor loss can contribute to:
o Familial leukaemias
o Therapy-related leukaemia
o AML in elderly
o Transformation of chronic leukaemia to an acute/blastic phase
4. The genetic basis of M3 AML; APML
Normal action of RARa and RA
• RARa uses Zinc to bind to the retinoid X receptor [RXR]; this dimer can bind to retinoic acid
response elements [RARE] on target genes
• This complex recruits NCoR/HDAC and Sin3; this is a repressor complex. It also interacts with
another repressor; SMRT
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