L03 - Basic concepts of hemopoiesis Flashcards
4 subtypes of hemopoiesis?
- Erthryopoiesis (RBC)
- Myelopoiesis (granulocyte, monocyte)
- Lymphopoiesis (lymphocyte)
- Thrombopoiesis (platelets)
Typical number and life span of RBC, WBC and Platelets?
- Red cells 5 x10’12/L 120 days
- White cells 4 x10’9/L 1 - 2 days
- Platelets 150 x10’9/L 8 days
List 4 stressors that can alter the rate of hemopoiesis?
Pregnancy
Infection
Blood loss or hemolysis
Disseminated thrombosis
What are the 4 unique features of Hemopoiesis compared to normal somatic cell cycle?
- Self- renewal
- Multilineage differentiation and development potential
- High proliferative capacity
- Dormancy if process is not needed
All tightly regulated
HSC progenitors and lineages?
HSC»_space; MPP»_space;
1) Common lymphoid progenitor»_space; Pre-B or Pre- T»_space; B or T lymphocyte
2) Common myeloid progenitor»_space; Granulocyte, Macrophage, erythrocyte, Megakaryocyte
3 established clinical uses of HSC?
1) Autologous HSC transplantation = replace damaged HSC after high dose chemo-radiotherapy (i.e. plasma cell myeloma)
2) Allogeneic HSC transplantation = replace diseased HSC (i.e. leukaemia)
3) Allogenic HSC transplantation for graft versus tumour effect (donor’s immune cells eliminate residual malignant cells)
General mechanism of control of hemopoiesis?
Regulated by growth factors (cytokines) and hormones
In Paracrine or endocrine fashion, bind to specific membrane receptors on hemopoietic cells
Affect proliferation, differentiation and maturation
List the 4 key hemopoietic growth factors?
- Erythropoietin (EPO) -> Erythropoiesis
- Granulocyte colony-stimulating factor (G-CSF) -> Granulopoiesis
- Granuocyte-monocyte colony-stimulating factor (GM-CSF) -> Granulopoiesis and monocytopoiesis
- Thrombopoietin (TPO) -> Megakaryopoiesis
Intracellular mechanism of haemopoietic regulation by cytokines?
Cytokine binds to specific cytokine membrane receptors on haemopoietic cells
> > janus kinase (JAK) phosphorylates STAT3
> > pSTAT3 dimerizes
> > translocates into nucleus and trigger transcription of CEBPB, PYC
Result of gain-of-function mutation of Jak2 on haemopoiesis?
constitutively active JAK»_space; myeloproliferative neoplasm
List 3 Therapeutic use of recombinant growth factors that regulate hemopoiesis?
– EPO use in end-stage renal failure
– G-CSF use in post-HSC transplant recovery and drug-induced neutropenia
– TPO receptor agonists use in autoimmune thrombocytopenia and aplastic anaemia
How does PKD lead to a certain haemopoietic disease?
Polycystic kidney disease
> > EPO hypersecretion
> > over-stimulation of JAK (hyperactivated) and increased erythtropoiesis
> > polycythemia/ erythrocytosis
Give one congenital disease of thromobopoiesis and its mechanism?
Congenital amegakaryocytic thrombocytopenia
Inherited loss-of-function mutation of TPO receptor
> > cannot activate JAK
> > cannot commit into megakaryocytic lineage
Endogenous source of G-CSF and GM-CSF and effect?
Both from endothelial cells, macrophages, fibroblasts
Increase G-CSF and GM-CSF secretion in response to infection/ inflammation to increase monocytopoiesis and granulopoiesis
Endogenous source of TPO (not thyroid peroxidase*) and effect?
Thrombopoietin: Made in liver, kidney
Normally bound to platelet to keep plasma TPO at low conc.
Decrease binding to platelet to increase plasma TPO to increase BM stimulation and production of platelets
What are the 3 compartments of the hemopoietic system?
1) Central hemopoietic organs: BM, thymus
2) Peripheral blood
3) Peripheral lymphoid organs: spleen, lymph nodes
General pathogenesis mechanism of hematological cancers?
Accumulation of clonal cells with acquired mutations:
1) Uncontrolled proliferation/ impaired apoptosis
2) Varying maturation failure»_space; abnormal mature cells and functionality
3) Suppression of other cells (e.g. BM suppression)
Compare the blast count, maturation, progess and presentation between Chronic and acute leukaemia?
Chronic leukaemia
- Blast <20%
- Slow progression
- Maturation not impaired, apoptosis impaired
- Insidious presentation
Acute leukaemia
- Blast >=20% in peripheral blood or BM
- Rapid progress
- Impaired maturation, uncontrolled proliferation, impaired apoptosis
- Rapidly fatal
Chronic leukaemia cannot transform into acute leukemia. T or F?
False
Chronic leukaemia can acquire different mutation»_space; transform into acute leukaemia
What does the pathological manifestation of hemotological cancers depend on? (3)
- cells or origin in the hierachy/ differentiation lineage
- ability of cancer stem cells to mature
- viability of maturing cancer cells in the marrow
Pathological manifestation of hematological cancer if HSC is affected? What if other progenitors are affected?
All lineage involved
» >An accumulation of maturing and mature cancer cells in marrow and peripheral blood involving multiple lineages
- Granulocytic/monocytic/ megakaryocytic/erythroid progenitor origin»_space; Myeloid lineages affected
- Lymphoid progenitors > Lymphoid lineages involved
Difference in manifestation between cancers cells that are able to fully mature and cancer cells that cannot mature?
Different stages of cancer cells are seen in the BM and blood:
Full maturation = see mature cells
Defective maturation = see blasts and decreased mature cells
Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Chronic myeloid leukemia?
mutated HSC - Multiple lineages involved with Effective maturation:
Maturing, Matured cancer cells seen in BM and peripheral blood
Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Acute myeloid leukemia?
mutated Granulocytic progenitor cell with totally blocked maturation:
Myeloblast accumulation in BM and blood, granulocyte and macrophage depletion
Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Myelodysplastic syndrome?
mutated Common myeloid progenitor cell affected with ineffective/ partial loss of maturation
- Accumulation of immature cells in BM, cytopenia + abnormal morphology
- Myeloid lineage affected: Granulocyte, macrophage, erythrocyte, megakaryocyte
Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in B-acute lymphoblastic leukaemia?
B-ALL:
- mutated Pre-B progenitor cell with blocked maturation
_ Lymphoblasts accumulate in BM and blood - B lymphocytes depletion
Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in chronic lymphocytic leukaemia/ lymphoproliferative disease?
mutated Mature B cells with maintained maturation state inside lymph nodes (impaired apoptosis, uncontrolled proliferation)
Mature B lymphocytes accumulate in BM and peripheral blood and LN
- B lymphocytes affected
