3.1 Myeloproliferative Neoplasms Flashcards
Normal haematopoiesis
- Normal haematopoiesis relies on the binding of a cytokine molecule e.g. _________________ to ligand receptors EPO-R, TPO-R, GCSF-R respectively
o This results in a signalling cascade that involves a variety of kinases and adaptor molecules – kinases activate downstream molecules by phosphorylation
- The signalling cascade activates the Janus kinase – phosphorylates ___________________________
o An activated STAT protein dimerises and entering the nucleus to bind to different sequences of DNA (STAT response elements)
o In doing so, they affect cell growth, cell differentiation and cell death
- Activated JAK-STAT pathway also activates signalling through other pathways such as
o ____________ – mitogen-activated protein kinase (MAPK) cascades, regulates cell cycle entry and cell proliferation
o PI3K-AKT – directly related to _____________________
erythropoietin (EPO), thrombopoietin (TPO), GCSF;
itself and a STAT (signal transducer and activation of transcription) molecule;
RAS-RAF-MEK-ERK;
cellular quiescence, proliferation, cancer, and longevity
Philadelphia chromosome negative MPNs include ________, _________ and ______________
Chronic myeloid leukaemia (CML) – individual, distinct MPN, characterised in all cases by the presence of a Philadelphia chromosome (or if absent in 5% of cases, presence of a _____________________ resulting in expression of the aberrant fusion protein)
Polycythaemia Vera (PV), Essential thrombocythemia (ET), Primary Myelofibrosis (MF);
BCR-ABL fusion gene
Philadelphia chromosome – involves human chromosome 9 and 22
- Chromosome 9 contains the _________ and chromosome 22 contains the _______________
- Chromosomal translocation may move the ABL region to chromosome 22 resulting in an edited chromosome 9 and 22
o Part of the _____________ of chromosome 9 exchanges with the ____________ of chromosome 22, resulting in a shortened chromosome 22 and a lengthened chromosome 9
- On chromosome 22, BCR is adjacent to the ABL region – juxtaposition results in the transcription and subsequent translation of the BCR-ABL fusion protein (201kd)
- BCR-ABL fusion protein contains a tyrosine kinase domain which is constitutively activated by its juxtaposition against the BCL protein – causing oncogenic activity as there is abnormal interaction and activation with many downstream molecules resulting in effects such as cell proliferation and promotion of survival
ABL;
BCR regions;
long arm; majority of the long arm;
Chronic myeloid leukaemia
- Seen in younger patients – median age about _____________ in Asia Pacific
o Male preponderance – ______ ratio in TTSH over 10 years
- Almost all patients present with leukocytosis – often very high WBC count
- Symptoms at presentation can be unrelated to leukocytosis in some cases but are related to
o Malignant condition – weight loss, fatigue, unexplained fevers
o Splenomegaly which is often pronounced – _____________________
o More often, symptoms are related to high white cell counts – sluggish blood flow in various organs
§ Brain or eye – _____________, confusion blurring of vision or a stroke-like condition
§ Pulmonary circulation – _____________
36 to 50 years;
5:3;
LUQ discomfort and early satiety from small meals;
headaches;
breathlessness
[CML-Parameters & clinical characteristics]
- WBC: 150* 10^9/L (normal range: _____ –> ___________)
- Hb: 10g/dL (normal range: _____ –> ___________)
- Platelets: 800*10^9 (normal range: _____ –> ___________)
- Others: differential counts will show the presence of a significant population of early myeloid cells such as _________________. ___________ is often also a feature.
Diagnosis: presence of ______________________
Peripheral blood smear
- Myelocytes: if fully differentiated will form _____________-
- Basophils: cells do not occur with such frequency usually
4-10x10^9; leukocytosis;
12-16g/dL; anaemic;
150-400*10^9L; thrombocytosis
myelocytes and promyelocytes;
Basophilia;
Philadelphia chromosome/ BCR-ABL mRNA
[Management of CML]
- Management of CML – target therapy for majority of patients against the abnormal tyrosine kinase activity of BCR-ABL proteins via tyrosine kinase inhibitors
o Drug molecule sits within the ___________ of the BCR-ABL molecule, inhibiting its action to phosphorylate multiple substrates in signalling cascades
- Tyrosine kinase inhibitors
o 1st Gen – ___________
o 2nd Gen – ___________
o 3rd Gen – _____
ATP pocket;
Imatinib;
Dasatinib/ Nilotinib;
Ponatinib
Polycythaemia Vera
- In more than 95% of patients, there is a point mutation in the gene coding for the JAK2 protein, resulting in the 617th _________ being replaced with _______________
o Leads to the loss of ____________________ of the pseudokinase domain on the kinase domain of the JAK2 protein
o Hypersensitivity of JAK2 to cytokine ligands or even constitutive activation of JAK2 (persistent downstream signalling)
o Consequence is the proliferation of _________________________
- Clinical characteristics – often seen in older patients, median age of ______________
o Male to female ration 1:1 in TTSH (although case series suggest male predominance)
o All patients present with erythrocytosis
- Symptoms at presentation may or may not be related to erythrocytosis
o Related to thrombosis such as strokes or myocardial infarctions, impaired microcirculatory blood flow leading to ______________________
o Associated symptoms are commonly due to presence of increased ____________ releasing more histamine – pruritis (especially aquagenic pruritis after a hot shower) and ________________
o Mild splenomegaly may be felt sometimes
valine;
phenylalanine;
autoinhibitory function;
all myeloid cell lineages – erythroid, granulocytic and platelet lineages;
62 years;
headaches and blurring of vision;
tissue mast cells ;
peptic ulceration
[Polycythaemic Vera]
- Sluggish blood flow in eyes resulting in _____________ (retinal haemorrhages may be seen
sometimes) - _____________ resenting as swelling and redness– commonly due to high proliferation and turnover of blood cells resulting in high ___________.
- _________________ – burning pain in fingers. Combination of red, warm and painful fingers or toes usually precipitated by _________________. Pathogenesis may be due to increased __________________ and a corresponding relative deficit in nutritive perfusion (steal phenomenon) with skin hypoxia
engorged retinal veins;
Gouty arthritis;
uric acid levels;
Erythromelalgia;
ambient heat or exercise;
microvascular arteriovenous shunting of blood;
[Polycythaemic Vera]
- Clinical characteristics: leukocytosis with ____________________
- WBC: 15* 10^9/L (normal range: _____ –> ___________)
- Hb: 19g/dL (normal range: _____ –> ___________)
- Platelets: 600*10^9 (normal range: _____ –> ___________)
- _________: due to iron deficiency from marked increase in RBC production, depleting iron stores
- Diagnosis: Mutation of JAK2 V617F in the presence of ___________________, bone marrow features and serum EPO
thrombocytosis and marked erythrocytosis;
4-10x10^9; leukocytosis;
12-16g/dL; polycythemic;
150-400*10^9L; thrombocytosis;
Microcytosis;
suitably high haemoglobin and haematocrit
Calreticulin mutations – found in MPN (ET and MF) patients
- Normal calreticulin resides in the ER as a ____________ – a portion of gene is deleted or some base pairs inserted resulting in loss of a part of the protein
o Abnormal protein is retained inside the _______
o Abnormal calreticulin that is secreted acts as a rouge cytokine – binds to ____________ leading to downstream signalling and proliferation of __________
- A review of a small number of ET and MF patients over 4 years in TTSH shows about half and 2/3 of ET and MF patients diagnosed bears JAK2 V617F mutation respectively
o 1 out of every 6 or 7 ET and MF patients diagnosed in TTSH bears calreticulin mutations
chaperone protein;
ER;
thrombopoietin receptors;
megakaryotes
[Essential thrombocythemia]
- Clinical characteristics – often seen in older patients, median age of 60 years
o Male to female ratio ___________- (although case series suggest female predominance)
o All patients present with thrombocytosis
- Symptoms at presentation may or may not be related to thrombocytosis – majority of cases are unrelated and thrombocytosis is often found incidentally
o Related to thrombosis such as ______________, impaired microcirculatory blood flow leading to headaches and blurring of vision
o Splenomegaly is usually not observed
1:1 in TTSH;
strokes or myocardial infarctions
Myelofibrosis
- Clinical characteristics – often seen in older patients, median age of ____________
o Male to female ration 1:1 in TTSH
o Diverse presentations
- Symptoms at presentation may be related to
o Malignant condition – weight loss, fatigue, unexplained fevers
o Splenomegaly which is often pronounced – LUQ discomfort and early satiety from small meals
o Anaemia – usually found on presentation
o Incidental finding of _______________-, leukocytosis, thrombocytosis or occasional blasts in peripheral blood
late 60s;
unexplained mild anaemia
[Myelofibrosis]
- WBC: 15* 10^9/L (normal range: _____ –> ___________)
- Hb: 9g/dL (normal range: _____ –> ___________)
- Platelets: 500*10^9 (normal range: _____ –> ___________)
- Others: _____________ (RBCs), ___________ – presence of early myeloid and erythroid cells
- Diagnosis: Relevant mutations (JAK2 V617F, calreticulin), supportive BM features, anaemia, leukocytosis, splenomegaly
- Note – leukoerythroblastosis is not diagnostic of MF alone as any process that replaces bone marrow will produce a similar picture. In MF, fibrosis replaces bone marrow. DDx includes ______________________
4-10x10^9; leukocytosis;
12-16g/dL; anaemia
150-400*10^9L; thrombocytosis;
Tear drop cells;
Leukoerythroblastosis;
metastatic cancer and multiple myelommas
Prognosis of thrombotic complications in Philadelphia chromosome negative MPNs
- PV and ET: Risk of progressing to ______ at a rate of 2-3% over 10 years; risk of progressing to MF at a rate of 5 to 6% over 10 years
- MF: Can transform from a pre-fibrotic phase to a fibrotic phase or present in the fibrotic phase. Risk of progressing to acute myeloid leukemia at a rate of 10 to 20% over 10 years
- Main prognostic work-up of ET and PV patients relates to risk of developing thrombotic complications such as stroke and ischemic heart disease
- _______________ is the highest predictor of risk of another thrombotic complication
- ______________ confers a higher risk of thrombosis than calreticulin mutations in ET
AML;
Prior thrombotic event;
JAK2 mutations
Management of PV and ET
- Especially for high risk patients with a previous history of thrombosis, it is important to keep platelet and WBC count in normal reference range
- Thrombotic risk reduction; Aspirin or other anti-platelets
- ____________ to aim for haematocrit <45% – in PV, a scheduled drawing of a quantity of blood for disposal
- Cytoreduction: Hydroxyurea most frequently used. _______________ for patients intolerant to hydroxyurea
Therapeutic venesection;
Alpha interferon
