Lecture 2: Haematopoiesis

Question 1

What regulates Haematopoiesis?

Answer 1

Cytokines
Transcription Factors (TFs)
Micro-RNAs (miRNAs)

Question 2

What are colony stimulating/growth factors (CSFs)?

Answer 2

Small secreted glycoproteins which mediate and regulate haematopoiesis

Question 3

What do CSFs do?

Answer 3

Bind to stem and progenitor cells and activate intracellular processes which causes proliferation and differentiation

Question 4

Cytokine ligands are made of ___________ with ____________________ pairs.

Answer 4

4 helix bundles with 2 pairs of antiparallel alpha helix pairs

Question 5

What are the defining features of Cytokine receptors?

Answer 5

S-S bonds due to Cysteine residues
Cytokine Receptor Homology Domain (CHD)
Conserved WSXWS domain

Question 6

What are the single chain receptors needed for haematopoiesis?

Answer 6

G-CSF
EPO
TPO

Question 7

What are the GP130 receptors needed for haematopoiesis?

Answer 7

LIF

IL-6

Question 8

What are βc receptors needed for haematopoiesis?

Answer 8

GM-CSF
IL-3
IL-5

Question 9

What is the function of Erythropoietin?

Answer 9

To act on the bone marrow to produce more mature RBCs

Question 10

Where is Thrombopoietin (Tpo) produced?

Answer 10

Liver
Kidney
Striated Muscle
Stromal cells in the bone marrow

Question 11

Tpo is _____________________ when made in the liver

Answer 11

Augmented with IL-6

Question 12

What is the function of Tpo?

Answer 12

Regulates the differentiation of megakaryocytes and platelets

Question 13

Gene expression is controlled by __________ and therefore cell differentiation is affected by __________.

Answer 13

Transcription Factors

Transcription Factors

Question 14

How do Epo make more mature RBCs?

Answer 14

Acts on pro-erythroblasts and causes ribosome synthesis => Hb accumulation => Nuclear ejection

Question 15

What happens during the Commitment/Proliferation phase?

Answer 15

Growth and Transcription factors cause growth and differentiation of progenitor cells

Question 16

What happens during the Maturation phase?

Answer 16

The pro-erythroblast becomes unable to proliferate and undergoes cytoplasmic and nuclear alterations, it then divides 4-5 times and the nuclei are ejected (enucleation)

Question 17

How many Hb are in a RBC?

Answer 17

640 million

Question 18

Where are Haeme units made?

Answer 18

In the erythroid mitochondria

Question 19

How do platelets form?

Answer 19

1. Megakaryocytes become endomitotic (nucleus divides and cell grows but no cytokinesis)
2. Arm like projections grow
3. Platelets bud off

Question 20

What causes the rapid growth of leukaemia cells?

Answer 20

Chromosomal translocations cause changes in growth and transcription factors which cause rapid growth

Question 21

_____ and _____ have GP130 receptors

Answer 21

LIF and IL-6

Question 22

_____, ______ and ________ have βC receptors

Answer 22

IL-3, IL-5 and GM-CSF

Question 23

What is a transcription factor (TF)?

Answer 23

A protein involved in the process of transcribing DNA to RNA

Question 24

TFs bind to ______________________ and can cause _________________.

Answer 24

specific DNA sequences

cell differentiation

Question 25

What are the key TFs in erythro/myelo differentiation?

Answer 25

GATA2
LMO2
GATA1
KLF1
NF-E2
PU1

Question 26

What is GATA1 needed for?

Answer 26

essential for erythroid and megakaryocytes

Question 27

What is GATA2 needed for?

Answer 27

regulates the development and proliferation of HP stem cells; regulates the endothelin-1 gene in endothelial cells

Question 28

What is LMO2 needed for?

Answer 28

required for yolk sac Haematopoiesis

Question 29

What is KLF1 needed for?

Answer 29

important for regulation of β-globin production

Question 30

What is NF-E2 needed for?

Answer 30

essential for regulating the differentiation of erythroid and megakaryocytes

Question 31

What is PU1 needed for?

Answer 31

involved in the differentiation or activation of macrophages or B-cells

Question 32

What are the key components of the JAK-STAT pathway?

Answer 32

 βC R chain activates JAK2 kinase leading to STAT activation
 This activates many pathways like raf-MAPK pathway, PI3-K pathway
 Leads to differentiation and proliferation

Question 33

Briefly, summarise erythroid differentiation:

Answer 33

Committed cell → Ribosome synthesis → Hb accumulation → ejection of nucleus and organelles → Mature RBC

Question 34

What are the 2 phases of erythroid differentiation?

Answer 34

Commitment/Proliferation phase, Maturation phase

Question 35

What happens in the Commitment/Proliferation phase of erythroid differentiation?

Answer 35

Progenitor cells are induced by extrinsic (Growth Factors) and intrinsic (TFs) factors to expand and activate differentiation pathways

Question 36

What happens in the Maturation phase of erythroid differentiation?

Answer 36

 Pro-erythroblast becomes unable to differentiate and undergoes cytoplasmic and nuclear alterations
 Nucleus becomes dense and is ejected (enucleation)

Question 37

Summarise Megakaryocyte differentiation:

Answer 37

1. TPO induces HP stem cells to become Haemocytoblasts
2. Cells stop dividing and become endomitotic, increase in nuclear and cytoplasmic volume and ploidy
3. Differentiation continues to occur until it reaches the fully committed megakaryoblast stage
4. Arm like projections containing pro-platelets which eventually get released to form budding platelets

Question 38

What is a myeloproliferative disorder?

Answer 38

• Condition characterised by abnormal growth of RBC, WBC, and platelets
• Can live long after diagnosis
• i.e. CML

Question 39

What is anaemia?

Answer 39

• Decrease in RBC or Hb in the blood

- Caused by blood loss, haemolysis, and decreased or faulty RBC production

Question 40

What is leukaemia?

Answer 40

• Cancer of blood-forming cells

- 60% associated with translocations, others due to mutations affecting growth, differentiation, and apoptosis