Myeloproliferative Neoplasms

Question 1

MPN

Answer 1

Myeloproliferative Neoplasms

Result from acquired genetic changes to haemopoietic cells which perturb stem cell behaviour and result in overproduction of ≥1 myeloerythroid cell series
OR
Acquired clonal disorders where an abnormal haematopoetic stem cell transforms myeloid progenitors leading to overproduction of one or more types of myeloid cells

Pick your poison Joseph xx

Question 2

4 MPNs

Answer 2

Polycythaemia Vera
Myelofibrosis
Essential (1º) thrombocythaemia
Chronic Myeloid Leukaemia

Question 3

Diagnostic criteria for PV before 2005

Answer 3

A1, A2 and A3/4 OR A1, A2 and 2 of B

A1 = raised RBC mass
A2 = absence of cause of 2º erthyrocytosis
A3 = palpable splenomegaly
A4 = clonality marker
B1 = raised platelet count
B2 = neutrophil leukocytosis
B3 = splenomegaly on scanning
B4 = reduced serum erythropoietin

Question 4

Features of PV

Answer 4

Red facial appearance
Thromboembolic events in fingers
Hypercellular BM w/ many megakaryocytes

Question 5

Diagnostic criteria (before 2005) and features for ET

Answer 5

High platelet count
Low/normal RBC mass
No Philadelphia chromosome
No collagen fibrosis of BM

Ischaemic feet
Large abnormal megakaryocytes

Question 6

Diagnostic criteria (before 2005) and features for MF

Answer 6

BM fibrosis
Extramedullary haematopoiesis
Splenomegaly
Leukoerythroblastic blood picture
Absence of other MPD
Absence of condition associated w/ 2º BM fibrosis

Cachectic appearance
⬆️ reticulin fibrosis in BM
Blood smear shows classical teardrop shaped RBCs

Question 7

JAKSTAT Pathway

Answer 7

Extracellular ligands - cytokines or GFs - bind to their respective receptors on cell surface
Dimerisation of cytokine receptors -> activate JAKs
Phosphorylate each other and tyrosine receptors - create docking sites for STATS
STATs recruited, phosphorylated and dimerise via their SH2 domains
Translocate to the nucleus
Activate transcription of target genes
Interconnected with other pathways egRAS/MAPK, PI3K, and Akt

Question 8

How is JAKSTAT pathway inhibited?

Answer 8

SOCS proteins can bind to JAK and/or cytokine receptors
Inhibiting the activity of JAKs
Downregulating the pathway

Question 9

JAK2 domains and their roles

Answer 9

FERM - interact w/ cytokine receptors
SH2 - role in conformation conservation
JH2 - tyrosine kinase like domain
JH1 - tyrosine kinase activity

Question 10

JAK2 mutation

Answer 10

Chromosome 9 exon 14
G->T transversion -> V617F mutation
Disrupts autoinhibitory activity of JAK2

Question 11

Frequency of V617F mutation

Answer 11

PV - 97%
ET - 57%
MF - 50%

Question 12

Current diagnostic criteria for PV

Answer 12

A1 - raised RBC mass
Presence of JAK2 mutation

Question 13

CALR roles

Answer 13

Calreticulin
W/in ER - chaperone ensuring quality control of glycoprotein folding

Outside ER - roles in proliferation, apoptosis, phagocytosis, immunogenicity cell death

Question 14

CALR mutation

Answer 14

Exon 9

ET and MF

Question 15

ET current diagnosis

Answer 15

4 major criteria or 3 major and 1 minor

1. High PLT count
2. Proliferation mainly of megakaryocytes lineage
3. Not meeting WHO criteria for PV, PMF, BCR::ABL1 +ve CML, MDS, MN
4. JAK2, CALR or MPL mutations
5. Presence of clinal marker or no evidence or reactive thrombocytosis

Question 16

MF current diagnosis

Answer 16

3 Major and at least 1 minor

1. Presence of megakaryocytic proliferation and atypia, reticulin and/or collagen fibrosis grades 2 or 3
2. Not meeting WHO criteria for ET, PV, BCR-ABL1 , CML, MDS or other myeloid neoplasms
3. Presence of JAK2, CALR, MPL mutation or in the absence of these mutations, presence of another clonal marker or absence of reactive myelofibrosis

a.Anaemia not attributed a comorbid condition
b. Leucocytosis of 11 x 109/l
c. Palpable splenomegaly
d. LDH increased to above the upper normal limit
e. leukoerythroblastosis

Question 17

Survival of MF patients differ:

Answer 17

CALR> JAK2> MPL> Triple negative

Question 18

Ruxolitnib

Answer 18

Inhibitor of JAKSTAT pathway

Question 19

Discovery of mutations in MPNs means we can:

Answer 19

Identify acquired clones in MPN
Develop treatments which interfere with the clonal disease pathway
Simplify diagnostic criteria

Different clones may be associated with various phenotypes and prognosis