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hematology - pathophysiology

hematology - pathophysiology

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Published by: jmosser on Jan 19, 2010
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02/01/2013

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2
Hematopoesis
Hematopoeisis
(Gr.
haimato
, “blood” +
 poiesis
, “creation”):
The formation of blood cells in the living body
Stem cells
: can
self-renew
(proliferate) or
differentiate
 
 
Toti
potent: can regenerate
entire
 
organism
(incl. extraembryonic tissues)
 
Pluri
potent (e.g.
embryonic
stem cells): can regenerate
across germ layers
(no extraembryonic tissues)
 
Multi
potent (e.g.
adult
stem cells): can regenerate cell types
restricted by germ layer
 
 Zen thought of the lecture: Every time a stem cell divides, it’s still a stem cell but a little less so
(not stochastic)
Note on
engraftment 
: both progenitors & primitive (high quality) stem cells can give rise to
all elements
 ; the difference isin
how long they can reproduce
(lose graft after initial good result with low-quality stem cells)
Glossary 
 
Clone
: cell population derived from
single ancestral cell
 
CFU: Colony-forming unit
: represents the cell that gives rise to a
colony
(assayable growth
in vivo / in vitro)
o
 
E.g. CFU-S, spleen CFU (mouse low-quality hematopoietic stem cells, give rise to spleen colonies post-BMT-irradiation)
 
Colony-forming assay
: isolate mononuclear cells from marrow; let ‘em grow (clones)
 
 
CFU-GM
:
colony
forming unit granulocyte macrophage
: most differentiated
myeloid progenitor,
no self-renewal
o
 
White colonies on assay: makes white blood cells
 
BFU-E
:
burst-forming unit erythroid:
RBC progenitor
o
 
Red colonies on assay; making RBCs
 
CFU-Mixed
/
CFU-GEMM
: progenitor of both CFU-GM and BFU-E (probably like CFU-S)
o
 
Mixed coloration on assay; making WBC & RBC too
Malignancy 
Malignancy
: unregulated
clonal growth
; from 1+ mutations
Cancer stem cells
:
 
tumor initiating cell with
limitless
 
self 
-
renewal
,
limited
 
differentiation
 
 
Treatments often don’t target them
 
Leukemic stem cells
: mostly at
low-quality HSC
(myeloid precursor)
 
H
EMATOPOETIC
 
S
TEM
C
ELLS
 
(2 classes)
Most primitive
(“
 
high quality”)
 Myeloid
(“low quality”)
 Precursor to: All
lympho-hematopoeticlineages
Granulocytes
,
RBCs
,
platelets
, B-cells(?)
Disease Rarely
involved
Most
 
“stem cell disorders”
 
Engraftment Delayed
but
life-long Rapid
but
limitedPhenotype
CD34+/-, other markersmostly -,
smaller
 CD34+, other markers
+
,
largerAldehyde DH +++
+ (or
low
)
O
THER
P
LAYERS
(
IN
S
TROMA
)Growth factor/cytokine
 
Stimulates
 
Erythropoietin
(kidneys)
RBCThrombopoietin
(liver)
Platelets
,
HSC
 
Flt-3 Dendritic
cells,
HSC
 
Stem cell factor Mast
cells,
HSC
 
G-CSF PMNs
Pathways to malignancy(
KNOW THESE 
)
 
increased proliferation
 
block in apoptosis
(more common)
 
 
3
 Acquired Aplastic Anemia
 
Hypocellular
bone marrow,
severe pancytopenia,
often in young patients
 
Autoimmune
disorder:
CTLs
target
low-quality stem cells
 
o
 
Reduced CD34 stem cell pool
pancytopenia
 
Treatment:
 
cyclophosphamide
,
o
 
activated in liver, blows away lymphocytes
 
o
 
stops T-cell reaction against low-quality stem cells
 
o
 
High-quality stem cells are saved
(have
aldehyde DH
,inactivate cyclophosphamide)
 
Chronic myeloid leukemia
 
 
BCR-ABL
fusion protein (t9:22
 –
Philadelphia chromosome)
blocksapoptosis
 
Called a “myeloproliferative” disorder –
 
is really a “ myelo
-
accumulative disorder”
Diseases of Hematopoesis & where they come from
Notes about this crazy picture (down = more differentiation)
Top of the pyramid:
high quality
/
primitive
hematopoetic SC.
 
Few diseases
at this levelNext:
low quality / myeloid SC
.
 
MOST DISEASES
here.Third:
lineage-committed progenitors
(a bit more differentiated; like those
colony-forming units
).
 
Pediatric
diseases are in this category; possibly why they do better clinically (more differentiated)
 
Bottom:
mature / differentiated
blood cells.
 
Autoimmune
diseases attack these more differentiated cells;
lymphomas
come from here
Final random thoughts:
 
You can make human universal stem cells by transducing 4 genes into adult skin cells.
 
Remember: epigenetics is important too
 
Pathways
to
bone marrow failure
(KNOW THIS)
 
1.
 
Oncogenesis / mutations
 
(leukemia, MDS, dyskeratosis congenita)
 2.
 
Direct DNA damage
(radiation, benzene, chemo)
 
3.
 
Autoimmunity
(aplastic anemia, pure red cell aplasia)
 
4.
 
Viruses
(HIV, parvovirus)
 

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