Leukaemia Flashcards
describe the epidemiology of the cancer of blood/”white blood”
5% of all cancers are cancers of the blood.
Blood cancers are the most common cancers in men and women aged 15-24 and the main cause of death in 1-34.
what is the essential cause of leukaemia?
Disease of the bone marrow:
a series of mutations in a single lymphoid or myeloid stem cell (progeny of a pluripotent haematopoietic stem cells)
this leads to the overspill of abnormal cells into circulation
multiple mutations is a requirement
what are the progeny of myeloid stem cells?
1) erythroblasts–>erythroid
2) megakaryoblasts
3) myeloblasts–>granulocytic cells
4) monoblasts–>monocytes
what are the progeny of lymphoid stem cells?
Pre B lymphocyte–> B lineage cancer are 75%
Pre T lymphocyte–> T lineage cancer are 25%
how does leukaemia differ from typical cancers?
usually no solid tumours involved
- the cells affected in this cancer, normally move constantly around circulation and in and out of tissues
i. e. behave differently as they don’t have a permeant location like a lot of cancers
abnormal cells start to take over bone marrow cells and circuit freely (overflow) into the blood
what do normal haematopoietic stem cells do?
circulate in the blood and both the stem cells and the cells derived from them can enter tissues, and normal lymphoid stem cells recirculate between tissues and blood.
what is the issue with describing leukaemia like standard cancers due to the different behaviour of the cells involved? how are the cancers refer?
invasion/metastasis cannot be applied normally
- these cells in leukaemia are meant to be mobile
benign–> chronic
malignant–> acute (aggressive and leads to quick death if left untreated)
how can leukaemias be classified?
1) chronic or acute
2) myeloid or lymphoid
3) subclass
- lymphoid: B or T lineage
- myeloid: granulocytic, monocytic, erythroid or megakaryocytic
what are the main classes of leukaemia?
o ALL – Acute Lymphoblastic Leukaemia. o AML – Acute Myeloid Leukaemia. o CLL – Chronic Lymphocytic Leukaemia. o CML – Chronic Myeloid Leukaemia.
what are the important influences that contribute to the pathogenesis of leukaemia?
a series of mutations in a single stem cell: o Proto-oncogene mutations. o Novel gene creation – e.g. a chimeric or fusion gene. o Dysregulation of a gene – when translocation brings the gene under the influence of a promotor or enhancer of another gene. o TSG loss of function – deletion or mutation of both copies.
in those with tendency to have chromosomal breaks
what are the inherited causes contributing to leukaemogenesis?
o Down’s syndrome.
o Chromosomal fragility syndromes.
o Defects in DNA repair.
o Inherited defects of TSGs.
what are the environmental causes of mutation?
- Irradiation
- Anti-cancer drugs.
- Cigarette smoking.
- Chemicals – e.g. benzene.
what happens to cells in ACUTE leukaemias?
what is the cause often?
what do mutations usually affect?
- Cell continue to proliferate but they do not mature
- Often is due to the product of an oncogene affecting proteins
- mutations usually affect transcription factors that affect multiple genes in a dominant manner
- affect the ability of the cell to mature
remember that oncogenes tend to cause non-solid tumours
what is the consequence of cells not maturing but proliferating in AML?
Build-up of immature cells in BM and this overflows into the blood
Failure of production of normal functioning end cells such as neutrophils, monocytes, platelets, etc which are replaced by the leukaemic cells
how does CML differ to AML?
In CML responsible mutations usually affect genes encoding proteins involved in the signalling pathways from receptors (membrane receptor or cytoplasmic proteins) cml
In AML its transcription factors that are affected (further downstream to signalling pathway)
what happens to cells in CML?
Cell kinetics & function are not as seriously affected as in AML.
- however the cell becomes independent of external signals i.e. doesnt need GF anymore,
- there are alterations in the interaction with stroma (signalling affected)
- there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively
- maturation however still occurs, in CML they are functional
key point: signalling defect and reduced apoptosis
what is the essential difference between AML and CML in terms of end product?
AML = failure of production of cells, reduced end product
CML = failure to apoptose, increased production of cells
what is the essential difference between ALL and CLL?
- 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.
similar to myeloid leukaemias
what does the accumulation of abnormal cells lead to in leukaemia?
- Leucocytosis
- bone pain (acute - in children especially)
- hepatomegaly
- splenomegaly (megalies due to free movement of these cells)
- lymphadenopathy (if lymphoid)
- thymus enlargement (if T lymphoid)
- skin infiltration
what are the metabolic effects of leukaemia cell proliferation?
- Hyperuricemia and renal failure
- weight loss (metabolism redirection elsewhere)
- low-grade pyrexia
- hidrosis (sweating)
in which group of people is ALL most prevalent?
children
highest incidence at age 4
what does B-cell lineage ALL result from?
delayed exposure to common pathogen
(conversely, early exposure to a pathogen protects)
uncommon causes: (i) irradiation or exposure to chemicals in utero and (ii) mutagenic drugs.
what factors affect exposure to common pathogens which then affects the chance of developing B cell lineage ALL?
factors such as family size, new towns, socio-economic class, early social interactions and variations between countries affect the exposure
what is lost in CLL?
normal immune function
