Targeted Therapies and Leukaemia

Question 2

What do cancer cells express?

Answer 2

Cancer cells express the same molecules and proteins as the surrounding cells.

Question 3

What is necessary to detect in cancer cells?

Answer 3

It is necessary to detect the mutation driving the cancer cells, such as an oncogene that may be switched on (overexpression).

Question 4

What is the aim of targeted therapies?

Answer 4

The aim of targeted therapies is to identify ‘critical’ mutations.

Question 5

What are the goals of targeted therapies?

Answer 5

The goals are to limit growth and invasion/spread, increase specificity of effects, limit side effects, and prolong ‘quality of life’.

Question 6

What is required for identifying dysregulated molecules/pathways?

Answer 6

Genetic profiling of the cancer is required to identify dysregulated molecules/pathways.

Question 7

What must a cell undergo to accumulate mutations?

Answer 7

A cell must go through a series of different mutations that synergize to accumulate mutations.

Question 8

Is it easier to target overexpression or loss of function?

Answer 8

It is easier to target overexpression/activation than loss of function.

Question 9

What is a challenge in targeting cancer therapies?

Answer 9

The challenge is targeting endogenous molecules and ubiquitous pathways.

Question 10

What are researchers looking for in cancer therapies?

Answer 10

Researchers are looking for ‘different’ molecular changes, such as changes in nucleotides and amino acids.

Question 11

What is leukaemia?

Answer 11

Leukaemia is a disease that arises from the haemopoietic stem cells within the bone marrow.

Question 12

What are haemopoietic stem cells?

Answer 12

Haemopoietic stem cells are precursors for mature red and white blood cells.

Question 13

What characterizes the proliferation of cells in leukaemia?

Answer 13

Leukaemia is characterized by the unregulated proliferation of a clone of immature white blood cells.

Question 14

What effect does leukaemia have on normal cells in the bone marrow?

Answer 14

Leukaemia squeezes normal cells out of the bone marrow.

Question 15

How does blood appear in cases of leukaemia?

Answer 15

In cases of leukaemia, blood appears milky.

Question 16

How is leukaemias classified?

Answer 16

Acute or chronic
Divided depending on cell of origin
- Myeloid
- Lymphoid

Question 17

What are the symptoms of chronic myeloid leukaemias?

Answer 17

• Fatigue
  
  • Anaemia
  • Splenomegaly - swollen spleen
    Hepatomegaly - swollen liver
    Elevated number of white blood cells in blood count
    All stages of granulocyte differentiation on blood smear
    Hypercellularity of bone marrow
    Increased ratio of myeloid to erythroid cells
    Account for 20% adult leukaemia’s

Question 19

What are the three clinical phases of CML?

Answer 19

1) Initial chronic phase, fairly mild
2) Accelerated phase develops after 4 years
3) Acute leukemic phase - blast crisis - no functional white blood cells for the immune system

Question 20

Where do mutations in CML arise?

Answer 20

Mutations are thought to arise in stem or progenitor cells.

Question 21

What controls the rate of transcription?

Answer 21

The rate of transcription is controlled by promoter regions.

Question 22

What happens when transcription is high?

Answer 22

High transcription leads to lots of mRNA and lots of protein.

Question 23

What can occur with low transcription to high transcription?

Answer 23

It can lead to overexpression of a protein, e.g., oncogenes.

Question 24

What is the effect of tumor suppressors on transcription?

Answer 24

Tumor suppressors show high transcription to low transcription.

Question 25

What percentage of CMLs have a specific genetic translocation?

Answer 25

95% of CMLs have a reciprocal translocation between chromosomes 9 and 22.

Question 26

What fusion is generated by the translocation in CML?

Answer 26

The translocation generates a fusion between breakpoint cluster region (BCR) and Abl tyrosine kinase - BCR-ABL.

Question 27

Define CML

Answer 27

Blood cancer caused by a specific chromosomal abnormality that leads to the uncontrolled growth of white blood cells

Question 28

What is the key molecular event associated with Chronic Myeloid Leukemia (CML)?

Answer 28

The Philadelphia Chromosome.

Question 29

What type of genetic alteration creates the Philadelphia Chromosome?

Answer 29

A reciprocal translocation between chromosomes 9 and 22, written as t(9;22)(q34;q11).

Question 30

What fusion gene is created by the Philadelphia Chromosome?

Answer 30

BCR-ABL.

Question 31

What does BCR stand for in the BCR-ABL fusion gene?

Answer 31

Breakpoint cluster region (from chromosome 22).

Question 32

What does ABL stand for in the BCR-ABL fusion gene?

Answer 32

Abelson tyrosine kinase (from chromosome 9).

Question 33

What is C-Abl?

Answer 33

A proto-oncogene that encodes a non-receptor tyrosine kinase called ALB1.

Question 34

What are the functions of C-Abl?

Answer 34

Regulates cell growth and division, cell differentiation, response to DNA damage, and cell adhesion and migration.

Question 35

What activates C-Abl?

Answer 35

Ionising radiation or DNA damage, leading to its translocation to the nucleus.

Question 36

What happens in CML regarding the C-Abl gene?

Answer 36

A translocation fuses C-Abl with the BCR gene on chromosome 22, forming the BCR-Abl fusion gene.

Question 37

What is the effect of the BCR-Abl fusion protein?

Answer 37

It has uncontrolled tyrosine kinase activity, leading to leukemic cell growth.

Question 38

What is the role of nuclear c-Abl in DNA damage response?

Answer 38

Nuclear c-Abl is activated by DNA damage, such as from radiation or chemotherapy, and can promote DNA repair, cell cycle arrest, and apoptosis if the damage is severe.

Question 39

How does c-Abl interact with p53?

Answer 39

c-Abl works with the tumour suppressor p53 to trigger apoptosis in damaged cells.

Question 40

What is the tumour suppressor role of c-Abl?

Answer 40

In the nucleus, c-Abl generally acts as a protective factor, helping prevent cancer by eliminating damaged cells.

Question 41

Why is the balance between nuclear and cytoplasmic functions of c-Abl important?

Answer 41

The balance is crucial because mislocation or mutation can lead to oncogenic activity, such as BCR-ABL in chronic myeloid leukaemia (CML).

Question 43

What is the BCR-ABL protein?

Answer 43

The BCR-ABL protein is an 'always-on' tyrosine kinase.

Question 44

What does the BCR-ABL protein do?

Answer 44

It continuously sends growth signals inside the cell, without normal regulation.

Question 45

What are the consequences of BCR-ABL protein activity?

Answer 45

It leads to uncontrolled proliferation of white blood cells, reduced apoptosis, and accumulation of immature cells in blood and bone marrow.

Question 46

Which pathways are overactivated by the BCR-ABL protein?

Answer 46

The Ras-MAPK pathway, JAK-STAT pathway, and PI3K-PKB pathway.

Question 47

What does the Ras-MAPK pathway drive?

Answer 47

It drives cell growth.

Question 48

What does the JAK-STAT pathway drive?

Answer 48

It drives cell growth.

Question 49

What does the PI3K-PKB pathway promote?

Answer 49

It promotes survival.

Question 50

What is the TEL-PDGFRβ fusion?

Answer 50

A genetic abnormality where parts of two different genes fuse to create an abnormal protein that drives cancer, especially certain types of leukaemia and myeloproliferative disorders.

Question 51

How does the TEL-PDGFRβ fusion occur?

Answer 51

Through chromosomal translocation, where a piece of chromosome 5 (PDGFRB) and a piece of chromosome 12 (ETV6, also called TEL) swap places, resulting in a fusion gene: TEL-PDGFRβ (or ETV6-PDGFRB).

Question 52

What is the role of TEL in the fusion protein?

Answer 52

TEL (ETV6) is a transcriptional repressor normally involved in controlling gene expression.

Question 53

What is the role of PDGFRβ in the fusion protein?

Answer 53

PDGFRβ (Platelet-Derived Growth Factor Receptor Beta) is a receptor tyrosine kinase that signals for cell growth and survival.

Question 54

What happens when TEL and PDGFRβ are fused?

Answer 54

The regulatory part from TEL is lost or changed, and the PDGFRβ part becomes constantly active, leading to continuous signalling and uncontrolled cell division and survival.

Question 55

What diseases are associated with the TEL-PDGFRβ fusion?

Answer 55

Chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia (aCML), and other myeloproliferative disorders.

Question 56

What is a therapeutic target for the TEL-PDGFRβ fusion?

Answer 56

Imatinib (Gleevec) and other tyrosine kinase inhibitors (TKIs) can block PDGFRβ activity.

Question 57

How do patients with TEL-PDGFRβ fusion respond to treatment?

Answer 57

Patients often respond very well to tyrosine kinase inhibitors (TKIs).

Question 58

What is used to detect the condition?

Answer 58

FISH (Fluorescence In Situ Hybridization) and RT-PCR for BCR-ABL transcripts.

Question 59

What is karyotyping used for?

Answer 59

To see the Philadelphia chromosome.