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R .S . R i l e y , M .D ., P h .D .

B o n e M a r r o w P a t h o l o g y

P a r t 1

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Bone marrow basicsRed cell diseases

White cell diseasesOther diseases

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Bone marrow basicsHematopoiesisBone marrow structureObtaining bone marrowInterpreting bone marrow

Red cell diseasesWhite cell diseasesOther diseases

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The present work intends todemonstrate the physiologic

importance of the bone marrowand that it is an important organ

for blood formation which hasnot been recognized. It operates

continually in ade novo

formation of red blood cells

Ernst Neumann (1834-1918)

Neumann, E. Du role de la moelle desos dans la formation du sang. C. R.

Acad. Sci. (Paris) 68:1112-1113, 1869

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Stem cell - Cell type that canmaintain its own numbers bycell division and yet providedescendants that eventuallymature into the various bloodcells

The great debate

Dualist concept of Ehrlich

Monophyletic theory of Pappenheim

Debate lasted four decades

Artur Pappenheim (1870-1916)

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Hematopoietic stem cellMophologically unrecognizableUndergo self renewalCapable of multilineage maturationExpress stem cell antigen (CD34)

Committed progenitor cell

Mophologically unrecognizableMay lack self renewalIrreversible lineage committmentExpress CD34, CD38, HLA-DR

Blast cellFirst recognizable cell in lineage

Mitotically activeMature cell

Functionally activeMitotically inactiveErythroid, myeloid, megakaryocyticlines + lymphocytes, plasma cells,

etc.

Hematopoieticstem cell

Committedprogenitor cell

Blastcell

Maturecell

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StemCell

StemCell

2 4 8 16 32 12864 256 512 1024

C o m m i t t e

d

R e c o g n

i z a b l e Loss of proliferative

potential

Biochemical changes

Surface markers

Receptors

Adhesion molecules

Chromatin openness

Access to epigenetictranscription factors

Regulated by thehematopoietic cytokines

Tremendous reserve torespond to disease states

Loss of proliferative potential

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Parent Stem Cell

CommittedDifferentiating CellRenewedStem Cell

RenewedStem Cell

FullyDifferentiated Cell

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HematopoieticStem Cell

MyeloidProgenitor Cell

MultipotentStem Cell

Myeloblast

Neutrophil

Monocyte

Eosinophil

Basophil

MegakaryocytePlatelets

Erythrocyte

Plasma Cell

B Cell

Lymphoblast

LymphoidProgenitor Cell

NK Cell

Helper TCell

Thymus

Suppressor TCell

T CellPrecursor

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HematopoieticStem Cell

MyeloidProgenitor Cell

MultipotentStem Cell

Myeloblast

Neutrophil

Monocyte

Eosinophil

Basophil

MegakaryocytePlatelets

Erythrocyte

Plasma Cell

B Cell

Lymphoblast

LymphoidProgenitor Cell

NK Cell

Helper TCell

Thymus

Suppressor TCell

EPO

G-CSF

GM-CSF

IL-5

SCF

TPO

IL-3

IL-1

G-CSF

M-CSF

IL-1

TNF

IL-2

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Factor Major Site of ActionStem cell factor (SCF) Pluripotent cells

IL-3 Early progenitors (CFU-GEMM)

GM-CSF Myeloid progenitors (CFU-GM)

G-CSF Granulocyte precursor

M-CSF Monocyte precursor

IL-5 Eosinophil progenitors

Erythropoietin (EPO) Erythrocyte progenitors

Thrombopoietin (TPO) Megakaryocyte progenitors

IL-6 B cell precursors

IL-2 T cell precursors

IL-1, TNF Stromal cells

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Lajtha, L.G.The Common Ancestral Cell, 1980

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Regulated primarily by erythropoietin (EPO)

Erythroblasts - all erythroid precursors

Five generations can be recognized

Erythroblastic island - Macrophage +associated erythroblasts, nonparatrabecularMorphologic features

Occur in islands

Adhere tightly to each other

Round nucleiClumped chromatin, basophilic cytoplasm

Immature, homogenous in rapidlyregenerating or diseased marrows

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Cadiopulmonary functionHgb Concentration

O 2 AffinityAtmospheric O 2Blood Volume

Other Influences

O2 Delivery

Bone Marrow

Stem Cells

Reticulocytes

O 2 Sensor

EPOProduction

Kidney

R e d

C el l M

a s s E

r y t h r o p o i e t i n

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P r o n o

r m o b

l a s t

B a s o

p h i l i c

N o r m

o b l a s

t M y

e l o b l a s t

P o l y c h

r o m a t o

p h i l i c

N o r m o b

l a s t

O r t h o

c h r o m

a t i c

N o r m

o b l a s

t

R e t i c

u l o c y t e

E r y t h r o c

y t e

Stem Cell

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Four generations of cells

Adults produce 1-2 x 10 9 granulocytes/day

Progressive nuclear segmentation,acquisition of primary and secondarycytoplasmic granules

Myeloblasts adjacent to bony trabeculaeor arterioles

Regulated by GM-CSF, G-CSF, IL-3, IL-5,etc.

Mature granulocytes excrete regulatorysubstances that inhibit granulopoiesis

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M y e l o b l a

s t

Stem Cell

P r o m y e l o

c y t e

( P r o g

r a n u l o c y

t e )

N e u t r

o p h i l i c

M y e l o

c y t e

N e u t r

o p h i l

i c

M e t a m

y e l o c

y t e

N e u t r

o p h i l

i c

B a n d

S e g m

e n t e d

N e u t r

o p h i l

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Life Span- 8-10 Days

33% inspleen

67% inperipheral

blood