Haematooncology Flashcards
1
Q
What kinds of cancers come from different haematopoetic stem cell progenitors?
A
- myeloid progenitors - acute myeloid leukaemia
- lympoid progenitors - acute lymphoblastic leukamia
- immune cell (T or B cells)
- others - lymphoproliferative/myeloproliferative neoplasms in later progenitors
2
Q
How can we detect changes in genes and their expression?
A
- at the chromosome level with karyotyping
- at the DNA level with next-gen sequencing
- at the RNA level with RT-PCR
- at the protein level with flow cytometry
3
Q
What methods might be used to diagnose leukeamia?
A
- family history
- biopsy of bone marrow or lymph nodes
- blood testing
- PET or CT scanning
- genetic analysis at any of these levels
4
Q
How might a biopsy be looked at for diagnosis of cancer?
A
- morphology
- DNA or RNA sequencing
- karyotpying
- flow cytometry
5
Q
What makes acute myeloid leukaemia (AML) a good cancer to study?
A
- genetically less complex than many solid tumours
- many common mutations often seen - sterotype mutations often lead to the same other mutations
- e.g. DNMT3A being associated with NMP1 mutations and vice versa
- acquired chromosomal abnormalities in 60% can be used to classify AML type
6
Q
How has blood cancer diagnosis improved?
A
- in the past they were classified only by mrophology
- now classified by genetics - much faster and more accurate
- genetic testing isnt as possible in other parts of the world etc
7
Q
Give an example of an AML subtype defined by chromosomal abnormalities
A
- APML
- contains a translocation that results in a PML/RARA fusion protein
- severe and fast progressing but >90% survival if caught early
- highlights the importance of specific diagnosis
8
Q
How can the APML fusion protein be screened for?
A
- fluorescence in situ hybridisation (FISH) to detect specific sequences on chromosomes
- can mark PML and RARA with different markers and fusion proteins can be seen with both markers on one chromosme
9
Q
What does the PML/RARA fusion protein do in APML?
A
- PML promoter enhances RARA expression and reduces blood cell differentiation - get stuck as progenitors/precursors
- increases risk for cancer formation
- retinoic acid can be used to increase differentiation again but relapse is common
- retinoic acid doesn’t kill off the cells or change the genetic change but can allow differentiation and slow progression - early treatment to buy time for further treatments
- need to monitor those in remission to look for this
10
Q
What is NPM1?
A
- nuclear protein involved in centrosome duplication and the control of TSGs such as p53
- can shuttle into the cytoplasm but normally resides in teh nucleus
- mutations lead to an increase in its translocation into the cytoplasm and are associated with leukaemia
- for example mutations in nuclear export signals
- patients with NPM1 mutations driving their cancer have better survival than others
11
Q
What is FLT3?
A
- encodes a cytokine cell-surface receptor
- regulates differentiation, proliferation and survival of haematopoetic progenitors through PI3K, RAS etc
- activating mutations such as point mutations in its activation loop are seen in AML lead to constitutive signalling
- associated with poor prognosis
12
Q
Name 3 genes commonly mutated in AML
A
- FLT3
- NMP1
- DNMT3A
13
Q
How do NPMI and FLT3 mutations interact to cause different prognoses?
A
- NMP1 only = best prognosis
- both mutated = middle
- FLT3 only = worst prognosis
14
Q
What are hypomethylating agents to treat AML?
A
- DNMTs can result in epigenetic silencing
- gets converted and incorporated into DNA in place of cytidine
- DNMTs cant methylate them and TSGs are switched back on
- not a cure - used in relapsed disease or in those who cant deal with chemotherapy to extend life
15
Q
What needs to be considered in stem cell therapy for leukaemia?
A
- need to minimise excessive toxicity for patients with mutations in DNA repair mechanisms
- could eliminate the cancer but give them very high risk of malignancy further down the line or general toxicity
16
Q
How can FLT3 be targeted in AML treatment?
A
- combined with chemotherapy or alone as maintenance therapy
- type 1 binds the active receptor and blocks ligand binding
- type 2 binds the inactive receptor and causes a conformational change
17
Q
What is remission in cancer therapy?
A
- no cancer cells detectable
- morphological remission means there are no cells visible under a microscope
- molecular remission is more reliable
- relapse occurs after remission
18
Q
Why is monitoring important following cancer treatment?
A
- relapse is common
- response to treatments may wane so need to know if treatments need to be changed
19
Q
What is minimal residual disease?
A
- cancer cells are not detectable by standard methods
- are detectable by very sensitive methods
- stopping treatment here will lead to relapse
20
Q
What are the 3 key areas of cancer research?
A
- finding more effective, less invasive treatment, diagnosis and monitoring
- finding what mutations cause cancer
- what mutations alter a cancer’s response to different treatments
21
Q
What is personalized therapy?
A
- treatment personalised to the patient, the disease or ideally both
- combinations that minimise toxicity while maximising outcomes
22
Q
How can we try to detect very low levels of leukaemia cells in MRD? (3)
A
- multi-parameter flow cytometry to find patterns of protein expression seen in only leukaemia cells - works for most but not all have a characteristic protein phenotype and can look like normal progenitor cells in flow cytometry
- next generation sequencing works if you know the genotypes to look for
- or PCR to look for fusion proteins such as PML-RARA
23
Q
What is the 100K genomes project?
A
- taking samples of tumour DNA, germline DNA (usually blood, skin in leukaemias) and clinical data from those receiving cancer treatment in the UK
- creates a huge database of information
24
Q
What are the main challenges for the 100K genome project for haematological malignnancies?
A
- source of tumour and germline DNA
- rarity of diagnosis
