L03 - Basic concepts of hemopoiesis

Question 1

4 subtypes of hemopoiesis?

Answer 1

• Erthryopoiesis (RBC)
• Myelopoiesis (granulocyte, monocyte)
• Lymphopoiesis (lymphocyte)
• Thrombopoiesis (platelets)

Question 2

Typical number and life span of RBC, WBC and Platelets?

Answer 2

• Red cells 5 x10’12/L 120 days
• White cells 4 x10’9/L 1 - 2 days
• Platelets 150 x10’9/L 8 days

Question 3

List 4 stressors that can alter the rate of hemopoiesis?

Answer 3

Pregnancy
Infection
Blood loss or hemolysis
Disseminated thrombosis

Question 4

What are the 4 unique features of Hemopoiesis compared to normal somatic cell cycle?

Answer 4

1. Self- renewal
2. Multilineage differentiation and development potential
3. High proliferative capacity
4. Dormancy if process is not needed

All tightly regulated

Question 5

HSC progenitors and lineages?

Answer 5

HSC&raquo_space; MPP&raquo_space;

1) Common lymphoid progenitor&raquo_space; Pre-B or Pre- T&raquo_space; B or T lymphocyte
2) Common myeloid progenitor&raquo_space; Granulocyte, Macrophage, erythrocyte, Megakaryocyte

Question 6

3 established clinical uses of HSC?

Answer 6

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)

Question 7

General mechanism of control of hemopoiesis?

Answer 7

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

Question 8

List the 4 key hemopoietic growth factors?

Answer 8

• Erythropoietin (EPO) -> Erythropoiesis
• Granulocyte colony-stimulating factor (G-CSF) -> Granulopoiesis
• Granuocyte-monocyte colony-stimulating factor (GM-CSF) -> Granulopoiesis and monocytopoiesis
• Thrombopoietin (TPO) -> Megakaryopoiesis

Question 9

Intracellular mechanism of haemopoietic regulation by cytokines?

Answer 9

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

Question 10

Result of gain-of-function mutation of Jak2 on haemopoiesis?

Answer 10

constitutively active JAK&raquo_space; myeloproliferative neoplasm

Question 11

List 3 Therapeutic use of recombinant growth factors that regulate hemopoiesis?

Answer 11

– 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

Question 12

How does PKD lead to a certain haemopoietic disease?

Answer 12

Polycystic kidney disease

> > EPO hypersecretion

> > over-stimulation of JAK (hyperactivated) and increased erythtropoiesis

> > polycythemia/ erythrocytosis

Question 13

Give one congenital disease of thromobopoiesis and its mechanism?

Answer 13

Congenital amegakaryocytic thrombocytopenia

Inherited loss-of-function mutation of TPO receptor

> > cannot activate JAK

> > cannot commit into megakaryocytic lineage

Question 14

Endogenous source of G-CSF and GM-CSF and effect?

Answer 14

Both from endothelial cells, macrophages, fibroblasts

Increase G-CSF and GM-CSF secretion in response to infection/ inflammation to increase monocytopoiesis and granulopoiesis

Question 15

Endogenous source of TPO (not thyroid peroxidase*) and effect?

Answer 15

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

Question 16

What are the 3 compartments of the hemopoietic system?

Answer 16

1) Central hemopoietic organs: BM, thymus
2) Peripheral blood
3) Peripheral lymphoid organs: spleen, lymph nodes

Question 17

General pathogenesis mechanism of hematological cancers?

Answer 17

Accumulation of clonal cells with acquired mutations:

1) Uncontrolled proliferation/ impaired apoptosis
2) Varying maturation failure&raquo_space; abnormal mature cells and functionality
3) Suppression of other cells (e.g. BM suppression)

Question 18

Compare the blast count, maturation, progess and presentation between Chronic and acute leukaemia?

Answer 18

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

Question 19

Chronic leukaemia cannot transform into acute leukemia. T or F?

Answer 19

False

Chronic leukaemia can acquire different mutation&raquo_space; transform into acute leukaemia

Question 20

What does the pathological manifestation of hemotological cancers depend on? (3)

Answer 20

• cells or origin in the hierachy/ differentiation lineage
• ability of cancer stem cells to mature
• viability of maturing cancer cells in the marrow

Question 21

Pathological manifestation of hematological cancer if HSC is affected? What if other progenitors are affected?

Answer 21

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&raquo_space; Myeloid lineages affected
• Lymphoid progenitors > Lymphoid lineages involved

Question 22

Difference in manifestation between cancers cells that are able to fully mature and cancer cells that cannot mature?

Answer 22

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

Question 23

Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Chronic myeloid leukemia?

Answer 23

mutated HSC - Multiple lineages involved with Effective maturation:

Maturing, Matured cancer cells seen in BM and peripheral blood

Question 24

Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Acute myeloid leukemia?

Answer 24

mutated Granulocytic progenitor cell with totally blocked maturation:

Myeloblast accumulation in BM and blood, granulocyte and macrophage depletion

Question 25

Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in Myelodysplastic syndrome?

Answer 25

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

Question 26

Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in B-acute lymphoblastic leukaemia?

Answer 26

B-ALL:

• mutated Pre-B progenitor cell with blocked maturation
  _ Lymphoblasts accumulate in BM and blood
• B lymphocytes depletion

Question 27

Cell of origin, maturation, cancer cells seen in BM and peripheral blood, lineages involved in chronic lymphocytic leukaemia/ lymphoproliferative disease?

Answer 27

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