BIOLOGY 2F03 Chapter Notes - Chapter 9-11: Philadelphia Chromosome, Ionizing Radiation, Hyperuricemia
20 May 2018
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1. The genetic Pathogenesis of CML
The hallmark of CML is the Philadelphia chromosome, which is present in 95% of patients. In the
remainder, the BCR-ABL fusion gene forms via cryptic translocations involving other chromosomes apart
from 9 & 22
The Philadelphia chromosome
• Translocation of BCR (22q) to ABL (9q)
o The result is an elongated tyrosine kinase product which is constiutively expressed
• 15% of primary ALL patients have the same mutation, but the splice point on the BCR gene is
upstream - this produces a smaller gene product
• BCR/ABL expression in the HSC leads to:
o Proliferation & resistance to apoptosis of myeloid lines, particularly neutrophils
o Decreased development of lymphoid lineages
o Development into accelerated/blastic CML in the context of additional mutations
• ABL is usually a nuclear protein, but BCR-ABL is cytoplasmic - has the potential to effect a lot of
downstream processes directly
2.2 - ACUTE MYELOID LEUKAEMIA (AML)
1. Clinical features of AML
D - A clonal expansion of myeloid blasts in the BM or other tissues, where the percentage of blasts
reaches >20% of nucleated cells in the BM
I - 4/100k/year; accounts for 70% of adult acute leaukaemias
A - adults; median 60years
S - M>F (just)
G
A - Known risk factors include ionising radiation, benzene, smoking, chemotherapy and possibly
viruses
P
C s/s/e
• Features relating to BM failure/ replacement of normal cells in BM by leaukaemic clones
o Normocytic Anaemia (fatigue etc)
o Neutropenia (infections, mostly bacterial, watch out for sepsis)
o Thrombocytopenia (spontaneous bleeds from mucous membranes)
• BM expansion/ bone impinging on other tissues - Bone pain
• Features relating to infiltrates of leukaemic clones into other tissues
o Organomegaly, gyum hypertrophy, sarcoma
• Symptoms due to increased metabolism - B symptoms
• Symptoms relating to electrolyte imbalance following release of intraceullar contents after
cell death
o Hyperuricaemia, hyperkalaemia
o Hypocalcaemia
Investigations [see below]
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Document Summary
The hallmark of cml is the philadelphia chromosome, which is present in 95% of patients. In the remainder, the bcr-abl fusion gene forms via cryptic translocations involving other chromosomes apart from 9 & 22. A clonal expansion of myeloid blasts in the bm or other tissues, where the percentage of blasts: clinical features of aml. D reaches >20% of nucleated cells in the bm. 4/100k/year; accounts for 70% of adult acute leaukaemias. Known risk factors include ionising radiation, benzene, smoking, chemotherapy and possibly viruses. C - supportive treatments; antibiotics (infections), blood transfusions (hb), platelet transfusions (bleeding), resuscitate, rehydrate, allopurinol. M - chemotherapyto induce remission, differentiating agents (eg atra, arsenic trioxide) can be used in m3. Depe(cid:374)ds o(cid:374) (cid:272)lassifi(cid:272)atio(cid:374) (cid:271)ut (cid:858)(cid:374)or(cid:373)al(cid:859) prog(cid:374)osis aml is roughly (cid:1008)2% (cid:1009) year survival. Immunophenotyping (flow cytometry: morphology (blood film, cytogenetic analysis (fish, molecular genetics. Acute promyelocytic leukaemia; t15,17; dic; good prognosis if treated early.
