20.06.27 MPN

Question 1

What are myeloproliferative neoplasms

Answer 1

-Clonal haemtological malignancies derived from myeloid lineage

• Granulocytic cells= neutrophil, eosinophil, basophil
• Monocytic/ macrophage
• erythroid
• megakaryocytic
• mast cell lineages

Question 2

Difference between myeloproliferative neoplasms and myelodysplastic syndromes

Answer 2

• myeloproliferative neoplasms = Normal proliferation and effective maturation with excess mature cells in bone marrow (erythrocytes, granulocytes, platelets)
• myelodysplastic syndromes= mature blood cells in the bone marrow do not mature, so do not become healthy blood cells

Question 3

What is the common mechanism for MPNs

Answer 3

• Mutations leading to constitutively active protein tyrosine kinases.
• Leads to abnormal proliferation

Question 4

What age is peak incidence

Answer 4

50-70 years

Question 5

Incidence of MPNs

Answer 5

6-10 per 100,000

Question 6

What MPD is differentiated mast cells

Answer 6

• Systemic mastocytosis

- Mutations in KIT gene. D816V

Question 7

What MPD is differentiated red blood cells

Answer 7

• Polycythemia vera

- JAK2 V617F or exon 12

Question 8

What MPD is differentiated platelets

Answer 8

• Essential thrombocythaemia

- JAK2 V617F

Question 9

What MPD is differentiated eosinophils

Answer 9

• Chronic eosinophilic leukaemia.

- FIPL1-PDGFRA fusion

Question 10

What MPD is differentiated neutrophils

Answer 10

• Chronic myeloid leukaemia

- BCR-ABL

Question 11

What MPD is differentiated monocytes

Answer 11

• Chronic myelomonocytic leukaemia.

- KRAS and NRAS are mutated in 25–40% -TET2 in 40-50% of cases.

Question 12

General phenotypic characteristics of MPNs

Answer 12

-Splenomegaly, hepatomegaly.

Question 13

Presence of mutations in which gene gives a definitive diagnosis of MPN

Answer 13

• JAK2 (Janus 2 kinase)
• Non-receptor tyrosine kinase involved in JAK/STAT pathway
• Increases proliferation and survival of malignant cells and increased levels of inflammatory cytokines

Question 14

What is the most common JAK2 variant

Answer 14

• V617F or c.1849G>T p.(Val617Phe)
• Can be used to monitor treatment response
• Some haplotypes preferentially acquire V617F (causing familial predisposition)

Question 15

What two other genes are mutated in MPN

Answer 15

• MPL (myeloproliferative leukemia virus oncogene)
• CALR (calreticulin)
• PDGFRA/B (respond to imatinib) and FGFR1 (doesn’t respond to imatinib)

Question 16

Review of MPL gene

Answer 16

• Encode thrombopoietin, regulates the differentiation of megakaryocytes and platelets.
• Mutations causes constitutively active signalling of JAK/STAT, MAPK and PI3K
• Can occur concurrently with JAK2 mutations

Question 17

Review of CALR gene

Answer 17

• May play a role in transcription regulation
• Mutations cause a frameshift, replacing C-terminus
• Mutually exclusive for JAK2 and MPL.

Question 18

Causes of atypical CML (BCR-ABL negative)

Answer 18

-NRAS or KRAS mutations

Question 19

Diagnostic strategy for classic MPN

Answer 19

• Molecular exclusion of JAK2
• Cytogenetics to rule out Ph-positive CML and to identify fusion genes.
• FISH or RT-PCR for FIP1L1-PDGFRA with eosinophilia.
• NGS for CALR mutations.