Class notes
CML AND IMATANIB
- Course
- Institution
Lecture notes of 6 pages for the course Mechanisms of pathology at Aston (IMMUNOLOGY NOTES)
[Show more]
Seller
Follow
sarah21jan
Content preview
CML and IMATINIB. IMATINIB was the first tyrosine kinase inhibitors to be used clinically really
successfully and it has set a lot of groundwork for cancer particularly in lung cancer
where tyrosine cancer inhibitors have been important.
Leukaemia.
Leukaemia is the excessive proliferation of white blood cell precursors.
It is caused by the clonal proliferation of haematopoietic stem or progenitor cells.
In the case of CML, we think that it is the stem cell itself.
Clonal means that all of the cells in the blood are coming from an initial single
mutation in a single cell that has been exploited through proliferation.
Leukaemia is a problem because it will crowd everything in your bone marrow and
this means that the bone marrow cannot do its normal job of creating all the red and
white cells that we need to be healthy. Once you have even more, you end up
damaging other organs aswell, this is because the cells have to go somewhere.
Replacement of normal bone marrow by leukaemic cells and accumulation in
peripheral blood causing bone marrow failure (too few erythrocytes, neutrophils,
platelets) and infiltration of organs such as liver, spleen ect.
Symptoms of leukaemia.
Widespread and hard to diagnose.
Diagnosis does not come from symptoms but from blood smears.
If there are lots of undifferentiated cells this highlights that there is a problem.
To many monocytes or too many undifferentiated monocytes.
Chronic myeloid leukaemia.
CML predominantly affects the myeloid lineage and the erythroid lineage not the
lymphoid.
So, it does not really seem to affect T and B cells, and this is not very clear why.
Myeloid cells include neutrophils, eosinophils, basophils, megakaryocytes (from
which platelets are derived) and monocytes.
Typically, there is an excess of monocytes that we see in these patients.
Myeloid lineage expands in CML.
Neutrophils.
Basophils.
Eosinophils
There is an expansion of these lineages.
Clinical features of CML.
Incidence: 1 :1000,000
The known risk factors are ionising radiation.
There are 3 phases:
1. Chronic phase: this can last 4-5 years, and these patients are asymptomatic. And if
they are detected it is because they have had a blood test for some other reason.
Expansion of myeloid compartment but cells differentiate normally.
, 2. Accelerated phase: this can last for weeks or years: more immature cells are in the
blood.
3. Blast crisis: this can also last weeks to months and this is where immature cells will
dominate and they will take up more than 30% of the cells in the bone marrow or
the blood.
The mutations that you see as the disease progresses means that you accumulate
mutations, and it gets progressively harder to treat.
The role of Bcr-Abl in CML.
Molecular origin of CML.
CML results from a reciprocal translocation between chromosome 22 and
chromosome 9, this creates a short chromosome called the Philadelphia
chromosome.
As a result of this we generate a novel chimeric protein called, Bcr-Abl.
Novel means that it is not normally there, it is generated just because of the disease.
Chimeric means that it has come from 2 different genes that have been put together.
Bcr-Abl is a constitutively active tyrosine kinase. This means that it is on all the time.
BCR (break point cluster region) and the function of it is unknown.
ABL (oncogene; it is a cytoplasmic tyrosine kinase)
The translocation responsible for Bcr-Abl
There is a reciprocal translocation material from chromosome 22 goes to
chromosome 9 and vice versa.
This creates a short chromosome, which ca be easily seen under a microscope.
Bcr-Abl is a fusion protein
In Abl there is a breakpoint on chromosome 9.
In chromosome 22 the break will be in the gene bcr and it can break in multiple
places, all within the BCR gene.
We get chromosome 22 fused to chromosome 9, this then makes a protein that is
hybrid.
It has some of the exons from Bcr and some from Abl and together, they make a new
protein that shouldn’t even exist.
We have an exon intron structure to our gene, this makes these combinations and
recombination’s easy to do.
Because you can break things from the intron and bring in exons from another gene,
as long as you maintain the reading frame.
Different breakpoints in Bcr give rise to protein fusions of different lengths.
NLS lets Abl go into the nucleus, it consists of a DNA bidnign domain and an actin
binding domain.
Bcr, which is the breakpoint region, has a dimerization domain, it has an SH2 binding
domain.
The dimerization domain is key.
The different cancers pick up different amounts of Bcr, but what they have in
common is that they all pick up the dimerization domain.
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller sarah21jan. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $9.30. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
75632 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now