Genetics in Haematoncology II

Question 1

Symtoms of MPN

Answer 1

Often asymptomatic with incidental findings

But increased risk of thrombosis, often in unusual sites, risk of Acute leukaemia or fibrosis

Question 2

Findings in PCV

Answer 2

Raised Hb and HCT, much hihger RBC:Plasma ration, normal platelets

Question 3

Findings in ET

Answer 3

Raised platelets, normal HB and Hcy

Question 4

Describe frequency of JAK2 mutations in MPN

Answer 4

PCV 95%
ET 50-70%
PMF 40-50%

Question 5

What is JAK2

Answer 5

Non-receptor TK, responds to ctokine signalling e.g. TPO, EPO, GCSF

Question 6

What mutations often occur in JAK2

Answer 6

Exon 14 mutation at V617F causes constitutive phosphorylation and activation
Mutations in exon 12 can also ocur

Question 7

What mutation other than JAK2 commonly occurs in MPN

Answer 7

MPL (the TPO Receptor)
8% PMF
4% ET mutations

Question 8

What mutations other than JAKs or MPL occur in MPN

Answer 8

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

Question 9

Where do mutations in CALR usually occur

Answer 9

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

Question 10

Which MPNs does CALR occur in

Answer 10

ET and PMF

DOES NOT OCCUR IN PCV

Question 11

HOW do patients with CALR mutations differ from those with JAK2 mutations

Answer 11

These patients have higher platelet coutns
Lower HB
and lower risk of thrombosis

Question 12

Treatment of MPN

Answer 12

Venesection
Cytoreduction: Chemo, IFN, P32 (if old)
JAK2 Inhibitors

Question 13

What MPN has the worst prognosis

Answer 13

PMF median 3-7 years and up to 30% AML Risk

Question 14

What are the symptoms of NHL

Answer 14

enlarged lymph nodes
Bone marrow suppresion
B Symtpoms
Extra nordal manifestations
Spelno/hepatomegaly

Question 15

What type of NHL is more curable

Answer 15

High grade

Question 16

Why are B cells more common

Answer 16

AS normal B cell function relies on rapid proliferation and genetic recombination of the immunoglobulin gene

Question 17

What is the translcoation in follicular lymphoma

Answer 17

t(14:18) –> places the bcl-2 oncogene in the presence of the IgH promter causes enhacnes anti-apoptotis effects

Question 18

What are the 3 types of Burkitts

Answer 18

1) Endemic
2) sporadic
3) immune deficiency associatsedx

Question 19

What is the charactreristc histological appearance of Burkitts

Answer 19

Starry sky due ot plentiful aooptosis and dividing rapidly

Question 20

What mAB can be given to treat Burkitts

Answer 20

Rituximab to CD20 expressing B cells

Question 21

Does BUrkitts have a good prognosis

Answer 21

Yes >80% cure rate

Question 22

Targets in B NHL

Answer 22

B Cell receptor pathway
BCL-2 inhibitors
Epigenetic therapies 
Monoclonal AB
Agents targgeting the programemd cell death axis
Chimeric antigen receptor T cells

Question 23

How can we inhibit the PI3K pathway in BCR

Answer 23

Idelalisib

Question 24

How does PI3K work

Answer 24

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

Question 25

WHat epigenetic target do we have in haem malignancies

Answer 25

EZH2 inhibitors –> part of the PRC2 complex –> strong expression og EZH@ independent ofmutations found in some NHL

Question 26

HOw can we inhibit bcl2 ocerepxression

Answer 26

BH3 mimetics e.g. navitoclax and venteclax! Early examples were promising but they also caused thrombocytopenia!

Question 27

How many exons does JAK have

Answer 27

25 exons

Question 28

What additional mutations can occur in MPN neoplasms aprt from JAK2, CALR, MPL

Answer 28

TET2
ASLX1
CBL
FLT3

Question 29

What is TET2 mutated in

Answer 29

Key role in myelopoiesis

Mutated in PB and PMF. Mutations in ET can icnrease aggressiveness

Question 30

What is ASLXI mutated in

Answer 30

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

Question 31

What is CBL mutated in

Answer 31

CMML, JMML, CML, MF

Question 32

What is CBL

Answer 32

A protooncogene of which there are 3 mammalian homologues

Question 33

What is FLT3

Answer 33

A class3 receptor tyrosine kinase.