HIS03 Basic Concepts Of Haemopoiesis And Its Regulation Flashcards
Haemopoiesis
- Erythropoiesis —> Erythrocyte
- Myelopoiesis —> Granulocyte + Monocyte
- Lymphopoiesis —> Lymphocyte
- Thrombopoiesis —> Platelets
Life-span and number of blood cells
Red cells: 120 days, 5x10^12 / L
White cells: 1-2 days, 4x10^9 / L
Platelets: 8 days, 150x10^9 / L
Number is normally kept constant
—> Static state
—> but can change in response to physiological / pathological stress:
1. Pregnancy
2. Infection
3. Blood loss / Haemolysis
4. Disseminated thrombosis (many platelet consumed)
Origin of blood cells
Haematopoietic stem cell (bone marrow)
—> Asymmetrical division
—> **Self-renewal (initial stage) + **Differentiation/Development/Increase number (late stage)
***Properties of Haematopoietic stem cells
- ***Self-renewal capacity (make sure HSC number maintained in healthy amount)
- ***Multilineage differentiation potential
- Proliferation capacity (make sure HSC number maintained in healthy amount)
- Dormancy (cell division can be stopped according to physiological states)
—> Tightly regulated process
***Haematopoietic stem cells
1 in 20x10^6 human bone cells
**Clinical use:
1. Replace **damaged HSC after high dose chemo-radiotherapy (e.g. Plasma cell myeloma)
- ***Autologous HSC transplantation
—> HSC harvested from patient itself before chemo-radiotherapy
—> infuse back after
- Replace **diseased HSC (e.g. Acute leukaemia)
- **Allogeneic HSC transplantation - Provide **graft-versus-tumour effect (e.g. Allogeneic HSC attacks host body tissue including tumour)
- **Allogeneic HSC transplantation
Regulation of Haemopoiesis by growth factors
Cytokines
- Paracrine + Endocrine function
- Maintained at low basal levels, Upregulated during stress
- Binds to specific membrane receptors on blood cells
—> Effect on proliferation, differentiation and maturation
Key haemopoietic growth factors:
1. Erythropoietin (EPO) —> Erythropoiesis
2. Granulocyte colony-stimulating factor (G-CSF) —> Granulopoiesis
3. Granulocyte-Monocyte colony-stimulating factor (GM-CSF) —> Granulopoiesis and Monocytopoiesis
4. Thrombopoietin (TPO) —> Megakaryopoiesis
Control mechanisms on cytokines
Stimulate HSC to ***commit more in differentiation to a specific lineage
- Hypoxia —> ↑ EPO secretion from ***Kidney
- Infection / Inflammation —> ↑ G-CSF / GM-CSF secretion from **Endothelium, **Macrophage, ***Fibroblast
- Low platelet count —> ↓ binding of TPO produced from Liver and Kidney to platelet mass —> ↑ **unbound TPO in circulation —> stimulate production from **Liver, Kidney
Growth factor signaling pathway
Cytokines bind to cell surface receptor
—> activate JAK kinase
—> phosphorylate downstream protein (STAT family e.g. STAT3, STAT5)
—> translocate to nucleus
—> transcription of genes
—> proliferation, differentiation, maturation of blood cells
Clinical relevance of growth factors
Therapeutic use of recombinant growth factors:
- EPO use in anaemia due to end-stage renal failure
- G-CSF use in post-HSC transplant recovery + drug-induced neutropenia
- TPO receptor agonists is in autoimmune thrombocytopenia + aplastic anaemia
Diseases due to malfunctioning of growth factor signaling pathways
- Polycystic kidney disease (kidney structure damaged)
—> ***EPO hypersecretion
—> Over-stimulation of HSC to commit to RBC lineage + Speed up proliferation of RBC precursors
—> Erythrocytosis / Polycythaemia - Congenital amegakaryocytic thrombocytopenia
—> Inherited ***loss-of-function mutation of TPO receptor
—> No function despite TPO binding to receptor
—> No Megakaryocytes
—> No Platelets - Myeloproliferative neoplasm
—> Constitutional activation due to somatic ***gain-of-function mutation of JAK2 kinase
—> abnormal activation of JAK2 despite no cytokine binding
—> ↑ Proliferation of cells (e.g. Thrombocythemia, Polycythaemia)
Haemopoietic system has 3 compartments
- Bone marrow (most blood cells), Thymus (T-lymphocyte)
- Central haemopoietic organs / Primary lymphoid organ
—> produce all blood cells - Peripheral blood
—> contain all blood cells - Spleen, Lymph nodes
- Peripheral lymphoid organs
—> contain B-lymphocytes, T-lymphocytes
***Haematological cancers
Cancer: Accumulation of **clonal cells with acquired mutation
Leukaemia: Blood cancer —> **↑ WBC —> turn blood to white colour
- **Uncontrolled proliferation, **Impaired apoptosis
- Varying degree of ***maturation failure
- Abnormal function
—> ***Suppression of other uninvolved cells e.g. Anaemia, Thrombocytopenia (factory failure)
***Chronic vs Acute Leukaemia
Chronic Leukaemia (<20% blasts in PB+BM ALWAYS) (blasts: earliest precursor cell seen in microscope)
- more maturing / mature cells, slow progression
- **maturation (differentiation) is not impaired (impaired apoptosis —> uncontrolled proliferation)
- more **insidious onset
- can transform into Acute leukaemia (due to maturation failure)
Acute Leukaemia (blasts >= 20% in PB/BM)
- more blasts, fast progression
- ***impaired maturation + uncontrolled proliferation + impaired apoptosis
- rapidly fatal if untreated
Pathological manifestation of haematological cancers
- Cell of origin in the **hierarchy (i.e. potential **lineages involvement)
- Haemopoietic stem cell origin —> ALL lineages involved
- Granulocytic / Monocytic / Megakaryocytic/ Erythroid progenitor origin —> Myeloid lineages involved
- Lymphoid progenitors —> Lymphoid lineages involved -
**Ability of cancer stem cells to mature
—> Stages of cancer cells observed in PB+BM
- **Full maturation —> Mature blood cells seen
- ***Defective maturation —> ↑ in Blasts -
**Viability of maturing cancer cells in marrow
—> Effectiveness of maturation and **appearance in blood
- **Apoptosis of mature cells in marrow due to acquisition of mutation —> **Cytopenia seen in PB
Case study: What kind of Haematological cancer will it be?
- Oncogenic mutation(s) in a HSC which permit effective maturation
—> accumulation of maturing and mature cancer cells in BM/PB involving multiple lineages
—> ***Chronic myeloid leukaemia (in fact lymphoid lineage also involved, but no lymphocytosis, ∵ proliferation and differentiation still maintained normally with this type of mutation)
—> Thrombocytosis, Leukocytosis, Basophilia - Oncogenic mutation(s) in granulocytic progenitor cell which totally blocks maturation
—> accumulation of Myeloblasts in BM/PB
—> ***Acute myeloid leukaemia - Oncogenic mutation(s) in common myeloid progenitor cell which shows ineffective maturation (some mature cells undergo excessive apoptosis) + partial loss of maturation ability (not a total loss)
—> Hypercellular / accumulation of immature cells in BM (not to degree of acute leukaemia) + **Cytopenia in PB
(—> Chronic myeloid leukaemia???)
—> **Myelodysplastic syndrome - Oncogenic mutation(s) in a pre-B progenitor cell which blocks maturation
—> accumulation of lymphoblasts in BM/PB
—> ***B-acute lymphoblastic leukaemia - Oncogenic mutation(s) in a mature B cell in LN which maintains maturation state
—> accumulation of mature B lymphocytes in LN, PB, BM
—> ***Chronic lymphocytic leukaemia / other B lymphoproliferative diseases
