Myeloproliferative Neoplasms Flashcards
name the types of myeloproliferative anaemia and the gene change that causes them
- Chronic myelogenous leukaemia, BCR-ABL1- Positive (CML)
- Polycythaemia vera – JAK2 variation
- Essential thrombocythemia – CALR exon 9
- Primary myelofibrosis – CALR exon 9
describe how CML is caused
- CML – was the first malignancy where there was a genetic basis of understanding made - Philadelphia chromosome – found in analysing patients with CML – found that the translocation was present
- Part of chromosome 22 is broken of and attached to chromosome 9
- Get an extra long chromosome 9 and short chromsoem 22 (philadephia chromosome)
- As a result of this translocation a new gene was found on chromosome 22 BCR is present on chromosome 9 ABL is found
- When chromosome 22 and 9 join you get BCR-ABL – codes for a new protein which is a trysoine kinase – this is an enzyme which attach a phosphate from ATP onto a protein, they are molecular on and off switches – switched on and not switched off
- Led to the development of targeted therapy
name what can be used to treat CML
- Imatinib can be used to treat CML
What is CML characterised by
- Characterised by dysregulated and uncontrolled proliferation of mature and maturing granulocytic cells
By definition what does CML have to have
- By definition has to have the presence of T(9,22), the Philadelphia chromosome
What does the blood film of CML have to have
- Increased granulocyte seen at all phases of maturation
- Lots of neutrophils
- Myelocytes – cells that are on there way to developing neutrophils
- Basophils
What are the symptoms of CML
- Many asymptomatic
- B symptoms – fatigue, weight loss, night sweats
Systemic symptoms
- Fatigue
- Night sweats
- Malaise
- Weight loss
Splenomegaly – particular in CML
- Early satiety – compress on the stomach
- Left Upper Quadrant fullness/pain
Hyperviscosity - particular in CML
- Headache
- Blurred vision
- Fluid overload
- Thrombosis and haemorrhage
How do you diagnose CML
- FBC
- Blood film
- Bone marrow biopsy
- Chromsome G banding
- FISH
- reverse transcriptase qPCR
- Nap/LAP score
what would the different ways of diagnosing CML show
- FBC
- Blood film
- Bone marrow biopsy
- Chromsome G banding
- FISH
- reverse transcriptase qPCR
- Nap/LAP score
- FBC = Raised White cell count and basophilia
- Blood film
- Bone marrow biopsy – blasts
- Chromosome G banding – karyotype is determined – presence of the philidephalia chromosome
- FISH – presence or absent of the BCR-ABL gene – take a probe which is commercialy available that will bind to the ABL gene on chromosome 9 and BCR gene on chromosome 22 – under flourscent light it wil light up a certain colour – normally genes are not in close proximity so the two different lights (red and green) are separate but if the fusion gene is present the lights are together and you see yellow light
- Reverse Transcriptase qPCR – amplify the copies of the BCR-ABL gene and you will be able to monitor how much gene is present so you can treat them
- Nap/LAP score - - level of leuckocyte alkaline phosphatase (LAP) will be decreased
What is the Philadelphia chromosome
The Philadelphia chromosome (Ph) is the hallmark of chronic myeloid leukaemia (CML), also occurs in acute lymphoblastic leukaemia (ALL).
describe the structure of the Philadelphia chromosome
- The Ph-chromosome is a shortened chromosome 22 produced from a reciprocal translocation of chromosomes 9 and 22
- This translocation causes a fusion of ABL1 and BCR genes
what does BCR-ABL code for
•Encodes a tyrosine Kinase (an enzyme that can transfer phosphate group from ATP to a protein = on/off switch)
what does the tyrosine kinase coded for by BCR-ABL do
- Encodes a tyrosine Kinase (an enzyme that can transfer phosphate group from ATP to a protein = on/off switch)
- Is ‘Constitutively active’ – Does not require activation from, and is is unregulated, by cytokines (i.e does not switch off)
- Leads to uncontrolled, proliferation and cell division
- Also inhibits DNA repair – leading to genetic instability
what can be used for monitoring BCR-ABL transcript levels in real time
- RT - PCR
- Quantifies the precise amount of BCR-ABL positive RNA
- For normalisation the levels of BCR-ABL RNA are compared to expression of the control gene ABL
- Patients are monitored every 3 months
what is the treatment for CML
- Tyrosine kinase inhibitors to inhibit signalling therefore stopping uncontrolled proliferation of the cell
- Imatinib 1st generation trysoine kinase inhibitor and 2nd and 3rd TKI ) dasatinib, nilotinib)
- Some people do not respond to TKI – therefore chemotherapy used
- Chemotherapy for refractor/accelerated phase/Blast crisis
- Allogenic haematopoietic stem cell transplant
What is the prognosis for CML
- Now excellent in era of TKIs – normal life expectancy
- Ongoing trials for cessation of therapy
- Small proportion of patients are resistant to TKIs who need chemotherapy and bone marrow transplant
What is primary polycythaemia vera
- Clonal disorder that results in an increased production of red blood cells
- Seen an increase in red cell volume due to clonal malignancy of a marrow stem cell
what does primary polcythaemia vera look like on a full blood count
– raise in haemoglobin and raise in haematocrit present due to the increased in red blood cell volume
- Usually > RBCs but all 3 cell lines can be increased
what mutation does primary polycythaemia vera result from
- Results from JAK2 mutation – in 95% of cases
What is the median age of primary polycythaemia vera
- Median age is 60
What is the definition of haematocrit
– percentage of blood volume made out of red blood cells – normal is 55% (a rise can also be caused by dehydration)
what can cause a rise in haematocrit
False raise = dehydration
True raise = increase in red blood cell
