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
what can some leukaemias in children result from?
o Irradiation in utero. o In utero exposure to certain chemicals – Baygon, Dipyrone. o EBV. o Rarely – exposure to a mutagenic drug.
what are the two main cellular changes that occur in ALL?
accumulation of abnormal cells
crowding out of normal cells
what are the clinical features of ALL as a result of the accumulation of abnormal cells (direct effects due to proliferation)?
o Bone pain. o Hepatomegaly o Splenomegaly. o Lymphadenopathy. o Thymic enlargement. o Testicular enlargement (due to lymphoblastic infiltration)
what are the clinical features of ALL as a result of crowding out of normal cells (indirect effects due to replacement)?
o Anaemia
– fatigue, lethargy, pallor, dyspnoea, SOB
o Neutropenia
– fever and features of infection e.g. cough
o Thrombocytopenia
– bruising, petechiae, bleeding.
what are the haematological features of ALL?
o Leucocytosis with lymphoblasts in the blood.
o Anaemia (normocytic, normochromic).
o Neutropenia.
o Thrombocytopenia (low platelets)
o Lymphoblasts replacing normal bone marrow cells
what are the investigations that can be done in ALL?
o FBC with liver and renal function tests.
o Bone marrow aspirate.
o Cytogenic/molecular analysis.
o Chest x-ray.
o immunophenotyping (to confirm T or B lymphoid cells),
what is done in cytogenic analysis (on BM aspirate for example)?
Immunophenotyping
– find the lineage of the cells.
methods assess the prognosis of ALL so treatment can be determined depending on the genetic mechanism involved:
• Hyperdiploidy (many extra chromosomes) –>good prognosis.
• T(4; 11) –> poor prognosis.
what is the leukaemogenic mechanism in ALL?
o Formation of a fusion gene – ETV6-RUNX1.
o Dysregulation of a proto-oncogene
– TCL3 and TCRA.
o Point mutation in a proto-oncogene.
Only one of the fusion genes created in a reciprocal translocation will contribute to leukaemogenesis
how can the fusion gene ETV6-RUNX1 be detected using cytogenic and molecular analysis?
FISH
o Green probe for ETV6 and red for RUNX1.
o Fused colours give yellow.
give an example of where dysregulation occurs?
(10; 14) (q24; q11) – the TCL3 gene is dysregulated by proximity to the TCRA gene.
what are the 3 types of treatment involved in ALL?
1) supportive: blood products (red cells, platelets) to correct the effects of bone marrow failure
2) systemic chemotherapy (widespread disease): to kill off the cells of the leukaemic clone and permit normal cells to regenerate
3) intrathecal chemotherapy: to destroy small numbers of leukaemic cells in the cerebrospinal fluid
in poor prognosis cases, bone marrow (or other haemopoietic stem cell) transplantation may be needed.
what is involved in supportive treatment?
replace:
- red cells (anaemia)
- platelets (thrombocytopenia)
- antibodies and Antibiotics (infection due to neutropenia)
to address the effects of leukaemia cells replacing normal cells
how is intrathecal chemotherapy done?
Lumbar puncture done to inject chemotherapy into CSF
instead a high dose of drug capable of crossing the BBB can be given
why must treatment be systemic in most cases of leukaemia?
the disease becomes widespread very early
describe the survival rates in ALL treatment
Childhood ALL survival rates have been increasing gradually (75% can be cured)
Overall survival has been gradually been getting better:
Approx. 10-year survival was 10% in 60s, now it is 95%.
Event free survival shows a similar pattern -5%.
Leukaemia is not often a solid tumour… what is it ?
replacement of normal bone marrow cells with leukaemia cells
how common in leukaemia?
most common cancer in men and women aged 15-24 (young)
main cancer to cause death in those aged 1-34
how does chronic leukaemia behave?
they behave in a “benign” way
not aggressive/invasive
you can’t call it benign as there is no solid tumour
how does acute leukaemia behave?
they have in a “malignant” way
aggressive/invasive
you can’t call it malignant as there is no solid tumour
what is the precursor to granulocytes, monocytes, erythroid and megakaryocytes?
myeloid
why is acute lymphoblastic leukaemia (ALL) “lymphoblastic”?
the lymphoblasts can’t mature into B and T lymphocytes
what occurs in acute myeloid leukaemia?
- cells proliferate but don’t mature
- this means only few end cells exist
end cells= neutrophils, RBCs etc - usually a mutation of a transcription factor affecting multiple genes
what occurs in chronic myeloid leukaemia?
- opposite to AML as there are TOO many end cells
- this is due to reduced apoptosis
- cells have become independent of external signals
- mutation of a gene involved in signalling pathway eg. membrane receptor
what sort of mutation leads to AML?
mutation of a transcription factor affecting many genes
what sort of mutation leads to CML?
mutation of gene involved in signalling pathway e.g. membrane receptor or cytoplasmic protein
explains why apoptosis is reduced
level of mature cells in AML
low
level of mature cells in CML
high
describe the cell is CLL?
they are increased mature B and T cells but abnormal
which genetic features provide a good prognosis for ALL?
1) Hyperdiploidy
2) t(12;21)
what is hyperdiploidy?
extra copies of multiple chromosomes
provides a good prognosis
why must be FISH uses to look for a t(12;21)?
they resultant chromosome does not look any different
t(12:21) produces a good prognosis for ALL
trisomy 4 has the best good prognosis too
what genetic features leads to a poor prognosis of ALL?
t(4;11)
what physiological effects i.e. clinical features does crowding out normal cells in ALL have?
These are the effects of replacing normal cells with leukaemia cells:
- fatigue, lethargy, pallor, breathlessness [anaemia]
- fever, infection symptoms [neutropenia]
- bruising, petechiae, bleeding [thrombocytopenia]
what 2 things cause the signs and symptoms of leukaemia?
(i) proliferation of abnormal cells:
e. g. bone pain, hepatomegaly, splenomegaly and lymphadenopathy (the latter mainly in lymphoid leukaemias).
(ii) loss of function of normal tissues as a result of replacement by leukaemic cells:
e. g. loss of bone marrow function leading to anaemia, thrombocytopenia, neutropenia.
difference in CML and CLL?
CML produces functional end cells
CLL produces useless end cells (which then replace normal cell)
what oncogenic events gives rise to the leukaemic clone in ALL?
(i) formation of a fusion gene
(ii) juxtaposition to the promoter of a different gene
(iii) dysregulation of a gene by juxtaposition to enhancers of T-cell receptor genes.
net result is that a clone of cells continues to proliferate but cells do not mature or die. The clone thus expands progressively, replacing normal cells.
what are the effects of leukaemic clone expansion in ALL?
(i) The direct effects of the proliferation of the leukaemic cells:
(lymphadenopathy, hepatomegaly, splenomegaly, thymic enlargement (T-lineage ALL), bone pain, renal enlargement, testicular enlargement, cranial nerve palsies (meningeal infiltration), hyperuricaemia.
(ii) The indirect effect of leukaemic cell proliferation:
leads to replacement of normal bone marrow cells by leukaemic cells
(causing anaemia, thrombocytopenia, neutropenia).
what is thymus enlargement a sign of?
T cell lineage ALL
