Hematology-01/07/08 Principles Of Hematopoiesis

Front 1

What are the three basic requirements for hematopoiesis?

Back 1

1. stem cells and progenitor cells.
2. appropriate microenvironment (stroma) for stem cells.
3. hematopoietic growth factors/interleukins.

Front 2

What are two main abilities of stem cells or progenitor cells?

Back 2

1. dividing with self-replication.
2. dividing and differentiating.

Front 3

Explain the ability for self-renew.

Back 3

reproduce self; produce identical daughter cells; one cell can establish long term hemopoiesis in a whole animal.

Front 4

Discuss the differentiation potential of lymphohematopoietic stem cells.

Back 4

Can turn into all blood cell lineages. see page 3 for list.

Front 5

What mitotic stage are most lymphohematopoietic cels in?

Back 5

G0 with a very low poliferative rate.

Front 6

What are p170 in lymphohematopoietic stem cells?

Back 6

multi-drug resistance (MDR-1) transmembrane pump. It pumps out most toxins to protect the stem cell from damage.

Front 7

Where are lymphohematopoietic stem cells found in the embryo to birth?

Back 7

yolk sack, liver, spleen, lymph nodes, bone marrow. Most active in bone marrow at birth.

Front 8

What do the lymphohematopoietic cells give rise to?

Back 8

primitive multipotential progenitors (only understood in vitro.

Front 9

What do the primitive multipotential progenitors give rise to?

Back 9

lymphoid progeniotr and multipotential hematopoietic progenitor, termed CFU-GEMM (colony forming unit-granulocyte/erythroid,megakaryocyte/monocyte).

Front 10

Where are CFU-GEMM found?

Back 10

BM, PB, spleen, liver

Front 11

What do CFU-GEMM progenitors give rise to?

Back 11

Unipotential hematopoietic progenitors. These have restricted lineage potential.

Front 12

What type of self renewal ability do the unipotential hematopoietic progenitors have?

Back 12

None. They have no self renewal ability.

Front 13

What does the microenvironment of the bone marrow consist of?

Back 13

Consists of vascular endothelium, fibroblasts, macrophages, T-lymphocytes. Collectively called the marrow "stroma".

Front 14

What are the two main functions of the marrow stromal cells?

Back 14

1. synthesize series of growth factors (cytokines/interleukins) for grwth and differentiation.
2. synthesize and express adhesion molecules for attachment of stem and progenitor cells to the appropriate stromal cell mileau.

Front 15

Cytokines influence what type of cells?

Back 15

influence all types of cells (various stem and progenitor cells as well as the mature progeny). Often enhance the functional activity of the terminally differentiated progeny.

Front 16

Many growth factors for hematopoiesis are found on which chromosome?

Back 16

5

Front 17

What is the function of granulocyte-macrophage colony stimulating factor (GM-CSF)?

Back 17

-stimulates the CFU-GEMM and possibly the lymphohematopoietic stem cell.
-stimulates proliferation and maturation of CFU-GM
-Helps mature cells (makes granulocytes better at function).

Front 18

Where is GM-CSF produced?

Back 18

produced by the marrow stroma (activated T-cells, macrophages, endothelial cells, fibroblasts).

Front 19

What makes granulocyte colony stimulating factor (G-CSF)?

Back 19

made by monocytes, endothelial cells, fibroblast, and neutrophils.

Front 20

What is the function of G-CSF?

Back 20

induces proliferation of granulocytes from CFU-GM as well as the mature progeny.

Front 21

What is GM-CSF licensed as?

Back 21

Leukine.

Front 22

What is G-CSF licensed as?

Back 22

Neupogen and Neulasta.

Front 23

What are the functions of monocyte-colony stimulating factor (M-CSF)?

Back 23

stimulates the growth of progenitor cells with high predilection for macrophages/monocyte maturation.

Front 24

Why is there no licensed therapeutic drug for M-CSF?

Back 24

it induces production of IL-1 in macrophages. This causes symptoms.

Front 25

What is the function of FLT-3 ligand?

Back 25

1. stimulates lymphohematopoietc and multi-potential progenitors.
2. syndergizes with KIT-ligand and thrombopoietin.
3. stimulates generation of dendritic cells.

Front 26

What is the function of the KIT ligand? What else is it known as?

Back 26

stimulates the survival and growth of the primitive stem cells. AKA steel factor.

Front 27

What is the function of thrombopoietin?

Back 27

1. regulator of megakaryocytes and platelets.
2. co-stimulates CFU-GEMM (along with KIT ligand and IL-11.

Front 28

What is the function of erythropoietin?

Back 28

1. stimulates red cell production from BFU-E and CFU-E and inhibits apoptosis.
2. co-stimulates BFU-Meg with thrombopoietin.

Front 29

What is the function of IL-3? What makes it?

Back 29

1. multilineage stimulator.
2. produced by activated T-cells and NK cells.

Front 30

What are the major controllers for thrombopoiesis?

Back 30

IL-11 and TPO (as well as GM-CSF and IL-3 but less so than the first two).

Front 31

What is the sources of thrombopoietin (TPO)?

Back 31

major sources is the liver with some from the kidney.

Front 32

What is the level of TPO if there is a low platelet count?

Back 32

TPO levels is high. NOTE: high platelets counts are more complex and not fully understood in regards to TPO levels.

Front 33

How do platelets form from megakaryocytes?

Back 33

Sheer stress from teh flow of blood causes fragmentation of megakryocytes when they protrude into the marrow vessels.

Front 34

What is erythropoiesis initially dependent on (CFU-GEMM to BFU-E)?

Back 34

BPA (burst promoting activity) which is a mix of other cytokines and interleukins.

Front 35

What are subsequent maturation of erythropoiesis dependent on (BFU-E to CFU-E and CFU-E to pronormoblast)?

Back 35

EPO

Front 36

How is the EPO gene expressed?

Back 36

both constitutively active and inducible.

Front 37

Where is EPO made?

Back 37

peritublar interstitial cell in the kidney (also small amount in liver).

Front 38

What signals/conditions controls EPO production?

Back 38

Tissue oxygenation. HIF-1 alpha are induced by hypoxia. HIF-1 factor responsible for transcriptional activation of the EPO gene. Normal O2 causes HIF-1 alpha degradation.

Front 39

What is the relationship between Hb levels and EPO levels?

Back 39

inverse relationship. Decreased Hb correlates with increased EPO level.

Front 40

What are the functions of Erythropoietin (4)?

Back 40

1. bring CFU-E into the dividing pool.
2. prevent programmed cell death.
3. speeding up the maturation process.
4. allow early release of immature red cell precursors (i.e. reticulocytes, marro retics, orthochromic normoblasts).

Front 41

What other hormones potentiate the effect of erythropoietin (4)?

Back 41

1. androgen.
2. dexamethasone.
3. thyroid hromone.
4. growth hormone.

Front 42

What are 4 conditions that are associated with inappropriately low levels of EPO?

Back 42

1. Renal failure.
2. chronic inflammatory states (e.g. rheumatoid arthritis).
3. chronic infections (e.g. HIV)
4. cancer
the last three blunt EPO response.

Front 43

What are 3 conditions associated with appropriate increase of EPO?

Back 43

1. Hypoxia due to altitude.
2. lung disease.
3. abnormal Hb, left shifted O2 dissociation curve?

Front 44

What are two condition associated with inappropriately high levels of EPO?

Back 44

1. polycystic kidney disease?
2. cerebellar hemanogiomas (and other cancers).