BCH3042 Lecture Notes - Lecture 13: Chronic Myelogenous Leukemia, Receptor Tyrosine Kinase, Chromosomal Translocation
Lecture 13 – Chronic Myeloid Leukaemia (CML) and BCR/Abl
• Single oncogenic mutation causes CML
Chromosomal Rearrangement
• Many affect oncogenes or transcription factors
• Rearrange the regulatory and coding regions of these genes – gene product is
MORE active or expressed at higher levels
• Genetics alterations have important prognostic implications
• Leukemia – translocations activate genes in stem cells with multi-lineage and
self renewal capacity
• Translocation generated oncogenes transform committed progenitors
Chronic Myeloid Leukemia
• Novel drug therapies developed from understanding the molecular basis of
human cancers
• Consistent acquired genetic lesion involving chromosomal translocation
• Only detected in leukemic cells (20% of all)
• A Fatal disorder (3-5 years)
o Now curable with new therapies
• Affects patients in their 30s and 40s
• Diagnosis
o Single abnormal HSC
o Proliferation of immature white blood cells in bone marrow and
peripheral circulation – blood cell count
o Proliferation in myeloid series but not as primitive cells as seen in
acute leukemia (some differentiation)
▪ More aggressive cancer – less differentiated it is
▪ Chronic is more differentiated that acute leukemia
• Single genetic lesion in HSC – generates a fusion oncogene, BCR-ABL (non
receptor tyrosine kinase)
o Encodes a protein tyrosine kinase that is necessary and sufficient for
cell transformation
o Don’t have ligand binding site outside of cell, inside
o Access to neoplastic clone without need for invasive surgery
CML caused by ABL
• Bcr-Abl generated by chromosomal translocation at chromosome 9 and 22
(q34;q11)
3’ sequence from Abl1 proto-oncogene on chromosome 9 with 5’ sequence
from BCR gene on chromosome 22.
• SH3 domain on N-terminus: allow for substrate and protein-protein
interactions
• SH2 domain: allows for binding to phosphorylated tyrosine residues
• Abl resides predominantly in nucleus, and sometimes
cytosol
• c-Abl breaks off at chromosome 9 → rest translocates
and bind sto Bcr chromosome 22
find more resources at oneclass.com
find more resources at oneclass.com