244 - Stem Cells and Hematopoiesis

Question 1

Where is thrombopoietin produce?

Answer 1

Liver

Liver failure -> no thrombopoietin -> no platelets :(

Question 2

What causes myelodysplastic syndrome?

Answer 2

Accumulation of mutations in the hematopoetic stem cell genome

May be a combo of toxic chemicals, radiation, predisposition due to genetic abnormality

Question 3

What is the treatment for Fanconi Anemia?

Answer 3

Treatment: Stem cell transplant

• Ideally, do before leukemia develops
  
  • AML likely to develop in adolescence w/o transplant
• Head, neck, and/or lung cancer likely to develop later, even after successful stem cell transplant

Fanconi anemia: Hereditary autosomal recessive disorder due to a DNA crosslink repair defect

• Laboratory tests show pancytopenia and normocytic or macrocytic anemia.

Question 4

List 4 cytokines involved in myelopoiesis

Answer 4

• IL-3
  
  • produced by T cells
  • ​Prevents apoptosis in common myeloid progenitor (CMP)
• GM-CSF (granulocyte/monocyte colony stimulating factor)
  
  • CMP –> Granulocyte Monocyte Progenitor (GMP)
  • antagonizes GMP apoptosis
• G-CSF (granulocyte colony stimulating factor)
  
  • GMP -> PMN
• M-CSF (monocyte colony stimulating factor)

Question 5

Hematopoietic stem cells first differentiate into either common lymphoid progenitor cells or common myeloid progenitor cells

What kinds of cells will each of these lines eventually become?

Answer 5

• Common lymphoid
  
  • T cells
  • B cells
  • Differentiation occurs outside of the bone marrow niche
• Common myeloid
  
  • Megakaryocyte erythroid progenitors -> RBCs and platelets
  • Granulocyte monocyte progenitors -> Granulocytes, monocytes, eosinophils, basophils

Question 6

List 2 treatments for myelodysplastic syndrome

Answer 6

• Stem cell transplantation
  
  • In younger patients
• Nucleoside analogues (5-azacytidine)
  
  • Does not help if MDS has progressed to AML

MDS results from accumulation of mutations in the hematopoetic stem cell genome

Question 7

Which gene is mutated in Schwachman-Diamond syndrome?

List 3 manifestations of the syndrome

Answer 7

SDBS gene

Function unknown, but results in these manifestations in childhood:

• Bone marrow failure
• Exocrine pancreas failure (diabetes)
• Growth delay

Question 8

Is erythropoietin useful in the treatment of pernicious anemia?

Answer 8

No

• Definitely useful in renal insufficiency or after chemotherapy*
• Maybe useful in myelodysplastic syndrome or early aplastic anemia*

Question 9

The mutation that causes Fanconi Anemia results in impairment of what cellular process?

Answer 9

Cross-link repair

• Cross-link repair is especially important during a stress response, in tissues where cell proliferation is upregulated
• 20+ proteins are involved, many different mutations possible

Question 10

What is the major growth factor that stimulates thrombopoiesis?

What is its effect? (receptor level)

Answer 10

Thrombopoietin (TPO)

• Interacts with c-mpl receptor on megakaryocyte erythroid precursor (MEP) cells
  
  • -> differentiation of MEP to megakaryocyte -> platelet

Basically, increases platelet production

Question 11

List 2 clinical scenarios in which hematopoietic cytokines are used therapeutically

Which cytokines are used?

Answer 11

• Renal failure
  
  • EPO is usually produced by renal parenchyma
  • Supplement to treat anemia in renal failure
• After chemotherapy
  
  • Use Granulocyte colony stimulating factor (G-CSF) to decrease severity of infections and need for transfusion
    
    • Shortens duration of febrile episodes by 3 days, but doesn’t improve morbidity or mortality
  • GCSF interacts with receptor on GMP to stimulate differentiation of GMP to PMN

Question 12

Which cells are produced in the process of myelopoiesis? (4)

Answer 12

Granulocytes, monocytes (innate immune system)

Also Basophils, eosinophils

Question 13

List 3 congenital disorders associated with hematopoietic stem cell dysfunction

Answer 13

• Fanconi Anemia
  
  • Ineffective cross-link repair
• Dyskeratosis Congenita
  
  • Telomerase dysfunction -> shortened telomeres
• Schwachman-Diamnond Syndrome
  
  • ​Mutation in SDBS gene

Question 14

How do the instructive and stochastic models of hematopoietic stem cell homeostasis differ?

Answer 14

Both models attempt to explain how hematopoietic stem cells (HCS) decide whether to differentiate or proliferate

• Instructive
  
  • Growth cell stimulation influences HCS activity (ex: Erythropoietin)
  • May make the most sense when the body is responding to stress
• Stochastic
  
  • Local factors in the niche influence HCS activity
  • May make the most sense during steady state

Question 15

List the 2 major causes of aplastic anemia

Answer 15

• Autoimmune: T-cell mediated
• Acute damage due to drugs or radiation
  
  • Ex: Cloramphenicol

Question 16

How can you differentiate between myelodysplastic syndrome (MDS) and aplastic anemia?

Answer 16

Bone marrow biopsy

• MDS will have abnormal biopsy
  
  • Results from chromosomal gains/losses in the hematopoietic stem cell pool
• Aplastic Anemia will have normal bone marrow biopsy at first
  
  • Will eventually evolve to “empty bone marrow

Question 17

The mutation that causes Dyskeratosis Congenita results in impairment of what cellular process?

Answer 17

Telomerase dysfunction -> shortened telomeres

• Results in symptoms similar to normal aging
  
  • Bone marrow failure
  • Skin/nail abnormalities
  • Leukoplakia -> head and neck cancer

Tx = stem cell transplant before bone marrow failure

Question 18

In myelopoesis, which cytokine promotes differentiation of the granulocyte myloid progenitor (GMP) to a polymorphonuclear cell (PMN)?

Answer 18

G-CSF

Granulocyte colony stimulating factor

Question 19

What skeletal abnormality is most common in Fanconi Anemia?

Answer 19

Malformation of thumbs

Question 20

List the 2 relevant types of cytokine receptors

How do they differ?

Answer 20

• Class I cytokine receptors
  
  • No endogenous kinase activity
  • Act as docking sites for proteins that are kinases
  • May form heterodimers (beta-common chain) or homodimers (hematopoietin)
• Class III cytokine receptor
  
  • Endogenous kinase activity - tyrosine kinase receptor
    
    • don’t require docking proteins
  • Ex: VEGF-R-like receptors

Question 21

What is the major growth factor that stimulates erythropoiesis?

What is its effect (on a receptor level)

Answer 21

Erythropoietin (EPO)

• Interacts with its receptor on Megakaryocyte erythrocyte progenitor (MEP) cells
  
  • -> Differention to RBC

Basically, promotes production of RBCs

Clinically useful in the tx of renal insufficiency and after chemotherapy

Question 22

What is the most serious possible consequence of a hematopoietic stem cell transplant in a patient with Fanconi Anemia?

Answer 22

Head, neck, or lung cancer later in life

Hematopoietic stem cell transplant will help with anemia, but mutation in Fanconi Anemia is present in all cells - head, neck, lung cells undergo high turnover, susceptible to cancer

Question 23

In myelopoesis, which cytokine promotes differentiation of the common myeloid progenitor (CMP) to a granulocyte myloid progenitor (GMP)?

Answer 23

GM-CSF

Granulocyte-monocyte colony stimulating factor

Question 24

In myelopoesis, which cytokine prevents apoptosis of the common myelpoid progenitor (CMP) cell?

Answer 24

IL-3