Chromosomal Aberrations Flashcards
Describe the philadelphia chromosome - what disease is it found in?
t(9;22) (q34;q11)
Part of tyrosine kinase ABL1 (on C9) moved to breakpoint cluster region gene (on C22)
Fusion protein that results has enhanced TK activity , is cytoplasmic and leads to increased phosphorylation of Y residues on cytoplasmic signalling molecules –> malignant phenotype.
CML (shorter chromosome).
What are the second generation defences?
Nilotinib - increased affinity for BCR-ABL1
Dasatinib or Bosutinib - broader TKI activity –> more rapid response.
Ponatinib - effective against CML with T315I mutation.
what is the function of Myc?
Growth promoting TF.
Forms heterodimers, binding E box sequences and recruiting HAT to control transcription of target genes.
Upregulates cyclins, down regulates Bcl-2
(can bind Mix-1, displacing p300 co-activator and repressing transcription of Miz-1 target genes)
How is Myc involved in B cell lymphoma?
Reciprocal translocation of Myc gene on C8.
Either t(8;14), t(8;2) or t(8;22)
Myc placed under control of highly active transcriptional regulators of Ig gene.
What is follicular lymphoma an example of?
Failure of apoptosis due to t(14;18) translocation –> constitutive expression of Bcl-2.
Outline the main features of CML.
Affects pluripotent haematopoietic stem cells and accounts for 15% leukaemia’s and may occur at any age.
WBC count elevated and presence of Ph chromosome seen in most cases.
Give another example of a fusion protein.
PAX3 = TF regulating muscle development –> alveolar rhabdomyosarcoma when PAX3 / FKHR.
How do recombinase mistakes lead to malignancies?
Recombinases join up adjacent pieces of DNA after excision of intervening sequences.
Recombinases recognise specific heptamer and nonamer sequences flanking gene segments.
Igs then undergo somatic hypermutation mediated by AID activation.
Mistargeting of AID –> B cell malignancy.
