L2: Haematological cancer Flashcards
cancers of the haemopoietic system
Cancers of the haematopoietic system
Definition:
Clonal diseases derived from a single cell in the bone marrow or peripheral lymphoid tissue that has undergone genetic alteration
Sometimes referred to as blood cancers or ‘liquid tumours’
Leukaemia: Characterized by circulating cancer cells and bone marrow involvement
Lymphoma: Cancer typically restricted to lymph nodes and other lymphoid tissue
Myeloma: Cancer affecting plasma B cells that accumulate in the bone marrow
Haematological cancers fall into acute and chronic forms
Acute: Often sudden onset
Chronic: Often indolent and may not be associated with any symptoms
Key difference between leukemia and lymphomas is that leukemias are circulating in the blood.
haematopoietic stem cells
Morphology: resembles lymphocytes
Phenotype (human): CD34+, CD59+, CD90+ CD38low, C-kit/CD117+
No single marker, combination of these markers. Low level of cd8
Increble potential to proliferate
Location in the bone marrow at 1 in 10,000 cells (rare)
Can produce 106 mature blood cells after x20 divisions
haematopoiesis
Quiscent self renewing haematopoetic stem cells —> oligo-potent and uni-potent progenitors —-> fully differentiated highly proliferated mature blood cells (red blood cells, white blood cells, platlets)
myeloid and lymphoid lineages
features and symptoms of haematological cancers + treatment
Features and symptoms of haematological cancers
Features:
Acquired mutations of clonal origin
Uncontrolled cell proliferation
Arrested cell differentiation particulary on myeloid lineage, cells get stuck and cannot diff into tumour cells?
Normal haematopoiesis prevented (known as Bone marrow failure)
Symptoms:
Unexplained weight loss
Unexplained bruising or bleeding
Unexplained fever
Drenching night sweats
Lumps or swellings
Enlarged lymph nodes
Persistent, recurrent, or severe infections (not enough immune cells)
Shortness of breath
Treatment
Chemotherapy
Radiotherapy
Haematopoietic stem cell transplantation (autologous (from patients own cells) or allogeneic-from a healthy donor)
Novel immunotherapies therapies
Monoclonal antibodies (examples: anti-CD20, anti-CD33)
Monoclonal antibody drug conjugates linking chemotoxic drug to ab
Bispecific T-cell engagers (BiTEs)
Chimeric antigen receptor (CAR) T cells
incidence rates of haematological cancers
Over 41,000 people diagnosed in the UK every year
Over 250,000 people living with blood cancer in the UK
Most common childhood cancer with over 500 diagnosed in the UK every year
Risk increases with age with just under 40% of patients aged 75 or over
Represent approximately 7% of all cancers with sightly higher frequency in males
genetic changes
- point mutations
- chromosomal changes
- epigenetic changes
3 types of chromosal changes- translocations, deletions and duplications
Epigenetic changes- dna itself unchanged but factors controlling expression of genes are dysregulated e.g: histone changes, methylation changes.
Frequency of point mutations in different cancers
Incidence of point mutations (single base pair added, deleted, or changed) is much LOWER in haematological cancers compared to solid tumours
Lung cancer, melanoma, liver cancer - high point mutations
Leukemias tend to have far fewer point mutations than other cancer types
Acute Myeloid Leukaemia – AML
Acute Lymphoblastic Leukaemia - ALL
Chronic lymphocytic leukaemia - CLL
Chromosal translocations associated with haemalotogical cancer
Point mutations-lower incidence in haematological cancer
Chromosome translocations- incidence higher in haematological cancer
>50% in leukemia >90% in lymphoma
Causes of genetic changes
Critical mutated genes in haematological cancers
Driver mutations confer selective growth advantage
Oncogenes such as BCL2 (suppress apoptosis), ABL1 and FLT3 (tyrosine kinases) and MYC (transcription factor)
Tumour suppressors such as TP53
Passenger mutations are neutral changes
Most cases are by chance aquisition.
specific risk factors for haematological cancers
Inherited factors. Some genetic disease such as Down’s syndrome where acute leukaemia occurs with 20-30-fold increased frequency (down syndrome-indicates people have chromosomal instability in their genome)
Chemicals: example benzene exposure can cause acute myeloid leukaemia
Cytotoxic drugs: example treatment with alkylating agents associated with increased incidence of chromosome loss (5q or 7q-) acute myeloid leukaemia
Infections: example Epstein-Barr virus and malaria association with Burkitt lymphoma
passenger and driver mutations
Passenger mutations do not confer change. Driver mutations cause malignant phenotype.
Fall into 2 categories: oncogenes
Bcl2- suppresses apoptosis
ABL1 and FLT3 tyrosine kinases overactive associated with cancer phenotypes
Myc - transcription factor. Overexpression drives.
Tumour suppressants
Tp53- expression required to suppress tumours. loss/reduced = increases chances of malignant phenotype developing.
A combination of point mutations and chromosomal transofmrations
clonal evolution
Haematological cancers are clonal diseases derived from a single cell (founder clone) that has undergone genetic change BUT genetic instability of cancer cells means multiple mutations can be acquired cumulatively over time giving rise to sub-clones
Blue and yellow cells: Normal
Orange: Founder clone with first ’hit’ driver mutation that has growth advantage but may be asymptomatic (pre-cancerous)
Brown, green and pink acquired additional ‘hit’ driver mutations that confer greater growth advantage and overtly cancerous behaviour
Linear evolution- one cancer clone
One of the yellow cells, aquired genetic change. Became orange. This is the founder clone. Not yet malignant. No symptoms. Sometimes called pre-cancerous. Founder clone acquires other genetic changes in this linear evolution pattern, additional mutation called a hit (driver) mutation. Brown clone- proliferate much faster. Clonal population.
Branched evolution:
Orange- founder population. Undergoes further mutations. Variety of different hit mutations. These clones can undergo more mutations. Multiple cancer sub-cloes that may have different phenotypes and behaviour. Different sub-clones from the founder give rise to the same disease.
example of clonal evolution progression to leukemia
Clonal haematopoiesis of indeterminate potential (CHIP)
Clonal cytopenia of undetermined significance (CCUS)
CHIP- clonal haemtopoesis of indeterminate potential (aquired genetic change e.g: DNMT3A mutation) do not know if patient will aquire more mutations that could lead to cancer——-> myelodysplastic syndrome (disease that does begin to develop symptoms when further mutations are awquired—-> high risk MDS symptoms are getting worse as disease progresses. Needs to aquire further mutations —–> acute myeloid leukemia. Gained NRAS mutation, faster proliferation
About 30-40% of patients with MDS will eventually progress to AML
- look at image of examples
