34 Myeloproliferative Neoplasms Flashcards
MPNs
1) Myeloproliferative Neoplasms;
2) also called myeloproliferative disorders, or MPDs;
3) are a collection of blood disorders that are caused by mutations in bone marrow stem cells.
Is MPD and MPN the same?
Yes
Characteristics of MPNs
1) abnormal and excessive production of one or more of myeloid cell lines:
granulocytes,
erythrocytes,
platelets,
2) No marked alteration of cellular maturation;
3) vast majority of MPN cases are sporadic: 5 in 100,000 individuals;
4) might have a familial predisposition in younger patients
WHO classified MPNs into two classes
1) Philadelphia chromosome (BCR-ABL1) positive: CML;
2) Philadelphia chromosome (BCR-ABL1) negative:
– polycythemia vera (PV);
– essential thrombocythemia (ET) ;
– primary myelofibrosis (PMF);
Primary characteristics of PV and ET
1). increased production of red blood cells and platelets;
2). night sweats;
3). Fever;
4). pruritus;
5). splenomegaly;
6). predispose to thrombosis or hemorrhage;
7). could be a longer-term illness;
8). may progress into myelofibrosis phase;
Primary characteristics of PMF
1). progressive marrow fibrosis;
2). variable degree of megakaryocyte and granulocyte proliferation;
3). more sever than PV and ET
MPNs can progress into what disease?
1). Myelodysplastic syndrome (MDS);
2). Acute myeloid leukemia (AML);
% risk of transformation of MPNs to MDS or AML
1). 20% for PMF;
2). 4.5% for PV;
3). <1% for ET
JAK2
1) Janus Kinase 2;
2) mediates signal transducing downstream of various cytokine receptors implicated in erythropoietin receptor signaling and hematopoiesis;
3) a cytoplasmic tyrosine kinase
JAK2 V617F mutation (Valine to Phenylalanine)
1) somatic mutation;
2) located on exon 14 nt. 1849;
3) G to T substitution
JAK2 protein domains
1). FERM domain;
2). SH2 domain;
3). pseudokinase (JH2) domain - negatively; regulates JAK function
4). tyrosine kinase domain (JH1)
Function of JAK2 V617F in MPNs
1) constitutive activation:
JAK-STAT, PI3K, and AKT pathways;
MAPK and ERK pathway;
2) cytokine hypersensitive;
cytokine-independent growth;
% MPNs with JAK2 V617F
1) 95% of PV patients have JAK2 V617F;
2) 55% of ET;
3) 65% of PMF;
4) PV and PMF patients can have biallelic JAK2 V617F due to uniparental disomy (UPD), not in ET cases
What is uniparental disomy?
1) both members of a chromosome pair are inherited from one parent;
2) the other parent’s chromosome for that pair is missing
JAK2 exon 12 mutations
1) the remaining 5% of PV patients that are JAK2 V617F negative have JAK2 exon12 mutations;
2) constitutive activation of erythropoietin signaling led to myeloproliferative phenotype;
3) only found in PV;
4) at least 37 different mutations located in codons 536-547;
5) mutually exclusive to JAK2 V617F
what kind of JAK2 exon 12 mutations are?
1) majority mutations are in-frame deletions of 3 to 9 bp;
2) 6-bp deletions are the most common;
3) substitution K539L;
4) in-frame duplications usually 33 bp in length
with respect to protein, JAK2 exon 12 mutations can be divided into 3 main types:
1). deletions that include E543;
2). amino acid substitution or deletion mutations that involve K539;
3). duplications of 10-12 amino acids that occur in the region of V536 to F547
JAK2 exon 12 mutations can be detected in what blood cell types?
granulocytes;
monocytes;
platelets;
rarely in lymphocytes
What is the predominate feature of patients with JAK2 exon 12 mutations?
erythrocytosis 紅血球增多症
What is MPL gene
the myeloproliferative leukemia virus oncogene;
located on chr. 1p34;
12 exons;
encodes the thrombopoietin receptor
What MPNs associated with MPL mutations?
ET (3%) and PMF (10%);
MPL mutations Not seen in PV
MPL mutations in ET and PMF
gain-of-function;
constitutive activation of thrombopoietin receptor without the binding of thrombopoietin ;
through JAK-STAT pathway;
on exon 10 (juxtamembrane domain);
two amino acids are affected: W515 and S505
amino acids affected by MPL mutations in ET and PMF
W515, S505
Majority of MPL mutations in ET and PMF
W515L, W515K
