Haemopoiesis Flashcards
Describe the locations of Haemopoesis throughout life
Foetus: yolk sac, liver/spleen then bone marrow
Infant: bone marrow of all bones
Adult: bone marrow in axial skeleton and end of femur
Describe the hierarchy of Haemopoiesis
Begins with a single unspecialised pluripotent stem cell which is capable of self-renewal or can become myeloid or lymphoid stem cell, which can then differentiate further into a functional cell. They can also undergo apoptosis as another fate.
Describe the different types of HSC division
Symmetrical or asymmetrical. Symmetrical produces 1 stem cell and 1 differentiating cell. Asymmetrical division produces either 2 stem cells or 2 differentiating cells (contraction/expansion of stem cell numbers)
What controls the balance of HSC division?
Environmental factors and internal cues from the cell itself (selected embryonic patterning pathways - Wnt, Notch, SHH etc.)
List the stromal cells of the bone marrow
- macrophages
- fibroblasts
- endothelial cells
- fat cells
- reticulum cells
What is leukamogenesis?
When a HSC/early myeloid/lymphoid cell undergoes a leukomogenic event (genetic mutation) resulting in clonogenic leukaemia cells (capable of dysregulated growth and differentiation). Proliferation of this clone occurs with differentiation blocked at an early stage resulting in a large number of immature and non-functional cells.
Describe myeloproliferative disorders
Clonal disorders which result in increased numbers of one or more mature blood progeny. Associated with JAK2 and calreticulin mutations. Possibility of becoming AML
What is an example of a myeloproliferative disorder?
JAK2 positive ET
- essential thrombocythaemia (bone marrow produces too many platelets) causing aggregation and increased risk of clots
- mutation of JAK2 (responsible for making protein that controls how many blood cells the stem cells make)
Describe myelodyspplastic syndromes
Disorders resulting in dysplasia and ineffective Haemopoiesis in 1 or more of the blood cells of the bone marrow.
- can be caused by previous chemotherapy/radiotherapy or acquired cytogenetic abnormalities
- may have increased levels of myoblasts
- characterised by progressive bone marrow failure
- some progress to AML
What is an example of a myelodysplastic syndrome?
Fanconi anaemia (AR inheritance):
- causes aplastic anaemia in a minority of cases
- causes somatic abnormalities, bone marrow failure, short telomeres, malignancy and chromosomal instability
What are the clinical effects of Fanconi anaemia?
- microphthlamia
- GU malformations
- GI malformations
- mental retardation
- hearing loss
- CNS problems (eg. Hydrocephalus)
Describe the genetic mechanism associated with Fanconi anaemia progression to cancer
- mutation occurs resulting in altered DNA damage response causing damaged cells to continue to be produced, an abnormal stress response, and the ups regulation of MAPKs
- MAPKs lead to the upregulation of TNF-alpha (inflammatory factor), which along with an abnormal oxidative stress response and environmental factors (which can increase risk of cancer) lead to genomic instability
- leading to the production of an FA cancer cell
What are the types of stem cell transplant and their indications?
- autologous: patient uses own blood stem cells (indicated in relapsed HL/NHL and myelomas)
- Allogeneic: stem cells come from donor (indicated in AML/CML/aplastic anaemia/hereditary disorders)
What are the types of stem cell donor?
- syngeneic: between twins
- Allogeneic: HLA match identical from sibling
- haplotype: a half matched family member
- umbilical cord
Describe the process of autologous stem cell transplant
- patient receives growth factor with or without chemo to make stem cells leave the bone marrow for collection
-mobilised peripheral blood stem cells are harvested by apheresis (blood is passed through an apparatus which separates out the stem cell sample and returns the remainder of the blood back into circulation) - Mozobil can be used alternatively to collect stem cells in patients who fail to mobilise
