246 - Stem Cells and Hematopoiesis Flashcards
Where is thrombopoietin produce?
Liver
Liver failure -> no thrombopoietin -> no platelets :(
What causes myelodysplastic syndrome?
Accumulation of mutations in the hematopoetic stem cell genome
May be a combo of toxic chemicals, radiation, predisposition due to genetic abnormality
What is the treatment for Fanconi Anemia?
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
List 4 cytokines involved in myelopoiesis
-
IL-3
- Prevents CMP apoptosis
-
GM-CSF (granulocyte/monocyte colony stimulating factor)
- CMP -> GMP
-
G-CSF (granulocyte colony stimulating factor)
- GMP -> PMN
- M-CSF (monocyte colony stimulating factor)
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?
-
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
List 2 treatments for myelodysplastic syndrome
- 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
Which gene is mutated in Schwachman-Diamond syndrome?
List 3 manifestations of the syndrome
SDBS gene
Function unknown, but results in these manifestations in childhood:
- Bone marrow failure
- Exocrine pancreas failure (diabetes)
- Growth delay
Is erythropoietin useful in the treatment of pernicious anemia?
No
- Definitely useful in renal insufficiency or after chemotherapy*
- Maybe useful in myelodysplastic syndrome or early aplastic anemia*
The mutation that causes Fanconi Anemia results in impairment of what cellular process?
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
What is the major growth factor that stimulates thrombopoiesis?
What is its effect? (receptor level)
Thrombopoietin
- Interacts with c-mpl receptor on megakaryocyte erythroid precursor (MEP) cells
- -> differentiation of MEP to megakaryocyte -> platelet
Basically, increases platelet production
List 2 clinical scenarios in which hematopoietic cytokines are used therapeutically
Which cytokines are used?
-
Renal failure
- EPO is usually produced by renal parenchyma
- Supplement to treat anemia in renal failure
-
After chemotherapy
- Use G-CSF to decrease severity of infections and need for transfusion
Which cells are produced in the process of myelopoiesis? (4)
Granulocytes, monocytes (innate immune system)
Also Basophils, eosinophils
List 3 congenital disorders associated with hematopoietic stem cell dysfunction
-
Fanconi Anemia
- Ineffective cross-link repair
-
Dyskeratosis Congenita
- Telomerase dysfunction -> shortened telomeres
-
Schwachman-Diamnond Syndrome
- Mutation in SDBS gene
How do the instructive and stochastic models of hematopoietic stem cell homeostasis differ?
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
List the 2 major causes of aplastic anemia
- Autoimmune: T-cell mediated
- Acute damage due to drugs or radiation
- Ex: Cloramphenicol