CasaD - Leukaemia Flashcards
What is leukaemia?
Cancer of the BLOOD
i.e. bone marrow disease
What occurs resulting in leukaemia?
Results from a series of mutations in a SINGLE
• LYMPHOID or MYELOID cell
What cells can be involved in leukaemia?
- Pluripotent hematopoietic SC
- Myeloid/lymphoid SC
- Pro-/Pre- T/B lymphocyte
What is different about leukaemia to other cancers in terms of tumours?
Most cancers exist as solid tumours but it is unusual for leukaemia patients to have tumours
• more often they have leukaemia cells replacing normal bone marrow cells and circulating freely
What is different about leukaemia to other cancers in terms of the cells involved?
Haemopoietic & lymphoid cells behave DIFFERENTLY to other body cells
- normal haemopoietic SC = circulate in the blood AND both the SCs & cells derived from them can enter tissues
- normal lymphoid SCs RE-circulate betw. tissues and blood
What does the difference about leukaemia mean about invasion and metastasis?
Invasion/metastasis can NOT be applied normally
• if ‘benign’ are called CHRONIC
• if ‘malignant’ are called ACUTE (aggressive & quick death if untreated)
How to classify leukaemia?
- Acute OR chronic
- Lymphoid OR myeloid origin
- Lymphoid - can be B or T lineage
Myeloid - can be combination of granulocytic, monocytic, erythroid OR megakaryocytic
Final classes of leukaemia?
ALL - acute lymphoblastic leukaemia
AML - acute myeloid leukaemia
CLL - chronic lymphocytic leukaemia
CML - chronic meyrloid leykaemia
Why do people get leukaemia?
An acquired genetic disease, resulting from SOMATIC mutation
Arises because of a series of mutations in a:
• single stem cell
• some from oncogenic influences
• others random errors that accumulate over time
Important leukaemogenic mutations that have been recognised?
• Proto-oncogene mutation
• Novel gene creation
- e.g. a chimeric OR fusion gene
• Dysregulation of a gene
e.g. when translocation brings the gene under influence of a promotor or enhancer of another gene
• TSG loss of function
- deletion or mutation of both copies
Inherited or other constitutional abnormalities can also contribute to leukaemogenesis - give examples
Down’s syndrome
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of TSGs
What is included in identifiable causes of leukaemogenic mutations
- Irradiation
- Anti-cancer drugs
- Cigarette smoking
- Chemicals - benzene
Explain AML?
Acute Myeloid Leukaemia
Cell continue to proliferate BUT they do not mature, leading to:
Build-up of immature cells
Failure of production of normal functioning end cells such as neutrophils, monocytes, platelets, etc.
o Responsible mutations usually affect TFs so transcription of multiple genes affected
o Often is due to the product of an oncogene affecting proteins
Explain CML
Chronic Myeloid Leukaemia
o Responsible mutations usually affect genes encoding proteins (membrane receptor or cytoplasmic proteins) involved in the signalling pathways from receptors
Cell kinetics & function are not as seriously affected as in AML
BUT cell becomes independent of external signals, alterations in its interaction w. stroma, there is still reduced apoptosis and the cell progressively expands in population
Broad difference between AML & CML
AML
• FAILURE of production of cells
CML
• INCREASED production of cells
Difference between ALL & CLL
Acute/Chronic Lymphoid Leukaemia
Acute lymphoblastic leukaemia (ALL):
• Increase in very immature cells (lymphoblasts) with a failure of these to develop to mature B/T cells
Chronic lymphoid leukaemia (CLL):
• Leukaemic cells are mature but abnormal
How does leukaemia cause the disease characteristics?
Caused by an accumulation of abnormal cells leading to: • Leucocytosis • bone pain (acute) • hepatomegaly • splenomegaly • lymphadenopathy (if lymphoid) • thymus enlargement (if T lymphoid) • skin infiltration
What are the metabolic effects of leukaemia cell prolifration?
- Hyperuricaemia
- Renal failure
- Weight loss
- Low grade
- Fever
- Sweating
In leukaemia, what does crowding out of normal cells lead to?
• Anaemia
- e.g. fatigue, lethargy, pallor, dyspnoea
• Neutropenia
- e.g. fever & features of infection
• Thrombocytopenia
- e.g. bruising, petechiae, bleeding
What does a CT Scan of a person with AML look like?
Shows
Intraventricular Haemorrhage
What is a feature of CML?
Loss of normal immune fuction
• due to loss of normal T/B-cell function
Which group of people does ALL affect most?
Disease of CHILDREN
What does B-lineage ALL result from?
Delayed exposure to a common pathogen
OR, conversely
Early exposure to a pathogen protects
• e.g. study showed enterovirus infection gave protection
Some leukaemias in children can also result from?
- Irradiation in utero
- In utero exposure to chemicals (e.g. Baygon, Dipyrone)
- EBV
- Rarely - exposure to a mutagenic drug
Describe the clinical features of ALL resulting from accumulation of abnormal cells
o Bone pain o Hepatomegaly & splenomegaly o Lymphadenopathy o Thymic enlargement o Testicular enlargement
Describe the haematological features of ALL
- Leucocytosis with lymphoblasts in the blood
- Anaemia (normocytic, normochromic)
- Neutropenia
- Thrombocytopenia
- Lymphoblasts replacing normal bone marrow cells
Investigations done to see if someone has ALL
- FBC with liver and renal function tests
- Bone marrow aspirate
• Cytogenic/molecular analysis
Immunophenotyping
– find the lineage of the cells
These methods are useful for assessing the prognosis of the ALL
• Hyperdiploidy (many extra chromosomes) –> good prognosis
• T(4; 11) –> poor prognosis
• Chest x-ray
Explain the leukaemogenic mechanisms of ALL
Mechanism:
• Formation of a fusion gene (e.g. ETV6-RUNX1)
- Dysregulation of a proto-oncogene
- Point mutation in a proto-oncogene
How can the formation of a fusion gene be detected?
e.g. ETV6-RUNX1
Can be detected using cytogenic & molecular analysis - FISH
• Green probe for ETV6 and red for RUNX1
• Fused colours give yellow
Example of dysregulation?
t(10;14) (q24;q11)
The TCL3 is dysregulated by proximity to the TCRA gene
Treatment types for ALL?
SUPPORTIVE
• e.g. replace RBCs, platelets & Abs
SYSTEMIC CHEMOTHERAPY
INTRATHECAL CHEMOTHERAPY
What type of treatment should be given for leukaemia and why?
Systemic
As leukaemis disseminates EARLY in the disease (similar to metastasis)
Why does treatment for ALL vary?
ALL has many phenotypes depending upon mutation
