Genetics in Haematoncology II Flashcards
Symtoms of MPN
Often asymptomatic with incidental findings
But increased risk of thrombosis, often in unusual sites, risk of Acute leukaemia or fibrosis
Findings in PCV
Raised Hb and HCT, much hihger RBC:Plasma ration, normal platelets
Findings in ET
Raised platelets, normal HB and Hcy
Describe frequency of JAK2 mutations in MPN
PCV 95%
ET 50-70%
PMF 40-50%
What is JAK2
Non-receptor TK, responds to ctokine signalling e.g. TPO, EPO, GCSF
What mutations often occur in JAK2
Exon 14 mutation at V617F causes constitutive phosphorylation and activation
Mutations in exon 12 can also ocur
What mutation other than JAK2 commonly occurs in MPN
MPL (the TPO Receptor)
8% PMF
4% ET mutations
What mutations other than JAKs or MPL occur in MPN
CALReticulin mutations
CALR normally functions in the ER as part of quality control and in the cytoplasm as a regulator of proliferation, apoptopsos, phagocytsis and immune function
Where do mutations in CALR usually occur
In exon 9 –> +1 base pair frameshift mutation which replaces the C terminus with a novel protein sequency
Converts it from acidid to basic structure
Which MPNs does CALR occur in
ET and PMF
DOES NOT OCCUR IN PCV
HOW do patients with CALR mutations differ from those with JAK2 mutations
These patients have higher platelet coutns
Lower HB
and lower risk of thrombosis
Treatment of MPN
Venesection
Cytoreduction: Chemo, IFN, P32 (if old)
JAK2 Inhibitors
What MPN has the worst prognosis
PMF median 3-7 years and up to 30% AML Risk
What are the symptoms of NHL
enlarged lymph nodes Bone marrow suppresion B Symtpoms Extra nordal manifestations Spelno/hepatomegaly
What type of NHL is more curable
High grade
Why are B cells more common
AS normal B cell function relies on rapid proliferation and genetic recombination of the immunoglobulin gene
What is the translcoation in follicular lymphoma
t(14:18) –> places the bcl-2 oncogene in the presence of the IgH promter causes enhacnes anti-apoptotis effects
What are the 3 types of Burkitts
1) Endemic
2) sporadic
3) immune deficiency associatsedx
What is the charactreristc histological appearance of Burkitts
Starry sky due ot plentiful aooptosis and dividing rapidly
What mAB can be given to treat Burkitts
Rituximab to CD20 expressing B cells
Does BUrkitts have a good prognosis
Yes >80% cure rate
Targets in B NHL
B Cell receptor pathway BCL-2 inhibitors Epigenetic therapies Monoclonal AB Agents targgeting the programemd cell death axis Chimeric antigen receptor T cells
How can we inhibit the PI3K pathway in BCR
Idelalisib
How does PI3K work
Heterodimer comprosing of the regulatory and catalytic subunits
the delta and gamma from are expressed primarily in haematolymphoid organs which can allow for the targeting of treatment
WHat epigenetic target do we have in haem malignancies
EZH2 inhibitors –> part of the PRC2 complex –> strong expression og EZH@ independent ofmutations found in some NHL
HOw can we inhibit bcl2 ocerepxression
BH3 mimetics e.g. navitoclax and venteclax! Early examples were promising but they also caused thrombocytopenia!
How many exons does JAK have
25 exons
What additional mutations can occur in MPN neoplasms aprt from JAK2, CALR, MPL
TET2
ASLX1
CBL
FLT3
What is TET2 mutated in
Key role in myelopoiesis
Mutated in PB and PMF. Mutations in ET can icnrease aggressiveness
What is ASLXI mutated in
One of the most frequently mutated in malignant myeloid disease
ASLXI proteins associate with olycomb proteins and involved in transcriptional regulation –> mutations increase HOXA9 and HOXA10 –> these cooperate with NRAS and KRAS mutations –> myeloid malignancies
Also mutated in MPN; rare in Et and PMF but more frequent in PB
What is CBL mutated in
CMML, JMML, CML, MF
What is CBL
A protooncogene of which there are 3 mammalian homologues
What is FLT3
A class3 receptor tyrosine kinase.
