DiseaseDisease

acute leukemia

h i l k ichronic leukemialymphomamyelomamyeloma

Usual phenotypeUsual phenotype

precursor

diff ti t ddifferentiated

Total WBC> 60

Blast Pro Myel

leukemoidreaction

0 0 0

acuteleukemia

82 0 0

CML 2 8 13

CLL 0 0 0

l Meta Band Seg Lymph

2 13 82 3

0 3 10 5

18 20 37 2

0 1 1 98

Acute leAcute le

Major Categories• Major Categories:

ALL = acute lymphocytic, lymphoid or ly

versus

ANLL = acute non-lymphocytic leukemi- includes granulocytic, erythroid, a

ukemiasukemias

ymphoblastic leukemia

a = acute myeloid leukemia (AML)and megakaryocytic lineages

Acute Le

• imbalance betweendiff ti tidifferentiation

• majority of cells no– therapeutic dilem

eukemia

n proliferation and

ot dividing mma

Leukemias -damagedamage

• majority have visible c• majority have visible c• tumor-specific chromo

e ge.g.,– t(15;17) acute promyelo– t(9;22) chronic myeloidt(9;22) chronic myeloid– t(8;14) Burkitt’s lympho

- evidence of e to DNAe to DNA

hromosome abnormalityhromosome abnormalityosomal translocations,

ocytic leukemiad leukemiad leukemiaoma/leukemia

Types of Gen(DNA mu(

• rearrange• transloca• point mu• deletions• deletions

netic Damageutations))

ementsationstations

ss

Proto-on

• Human genes homologous wcause cancer in animalscause cancer in animals

– e.g., abl is homologous with geleukemia virus

• Protein product of proto-oncnormal function in humans:

– e.g., tyrosine kinase activity of – e.g., transcriptional regulation

• Conversion to oncogenes byor disturbed function

cogenes

with genes in viruses which

enetic material in the Abelson murine

cogenes may have an important

ablby myc

y mutational events → enhanced

Conversion of pConversion of pto onc

• Possible mechanisms– Unaltered gene produ– Altered gene product

»usually a fusion pro

proto oncogeneproto-oncogene cogene

uct (e.g., myc in Burkitt’s)

otein (e.g., bcr-abl in CML)

Gene Products

• Growth factors• Receptors for growth facto• Molecules involved in signg• Proteins that bind DNA an

(e.g., transcription factors)

s of Oncogenes

orsnal transductiond regulate nuclear functions )

Genetic damage • Causes

– radiation– carcinogens

» benzenechemotherap» chemotherapy

– hereditary chromosome d– hereditary disorders of Dy– viruses (eg, HTLV-I)

P t• Proto-oncogenes → oncoge• Inactivation of ‘tumor suppr

• Multiple events

in leukemias

disordersDNA repairp

enesressor genes’

Erythroid progenitor

Hemato-poietic

p oge to

Megakaryocytit

Lympho

Stem Cell progenitor

Lympho-hematopoieticStem Cell

GranulocyteMonocyte progenitorprogenitor

LymphoidStem Cell

T-cell progenit

B-cell progeni

RBC’s

te platelets

basophilsbaso-progenitor

neutrophil-progenitor

eosinophils

neutrophils

eo-progenitor

neutrophil progenitor

monocyte-progenitor

neutrophils

monocytes

tor T-cells

itor B-cells

Myelodysplastic Sy

• Usually elderly, sometimes • Variable cytopenias, often s• Macrocytic anemia common• Neutropenia and thrombocyNeutropenia and thrombocy• Morphological abnormalitie

– AnisopoikilocytosisNeutrophil hypogranularity and h– Neutrophil hypogranularity and h

– Macroplatelets– Hypolobated megakaryocytes– Increasing blast countIncreasing blast count

• Cytogenetic abnormalities (• Variable response to Epo, G• Evolution to ANLL

yndrome (MDS)

prior chemo- or radiotherapyseverenytopeniaytopenias

hyposegmentationhyposegmentation

(esp. chromosomes 5, 7, 8)GCSF, hypomethylating agents

Oncogene Trans-Translocation Disease

t(8;14) some B-cell lymphomas, ALL

t(9;22) CML,some ALL

t(15;17) acute promyelocytileukemia

ActivationProposedProposed mechanism

↑expression of transcription factor (myc) chimeric signalling molecule (bcr-abl)

c chimeric transcription factor (pml-rarα

Acute Promyeloy

• about 7% of all ANLL

• malignant clone shows

• cells often contain multi

• disseminated intravascu

• t(15;17) almost always p

• sensitivity to arsenical t

ocytic Leukemiay

early differentiation

iple Auer rods

ular coagulation common

present

trioxide and retinoic acid

Acute Promyelocyticy y

• retinoic acid receptor-α (RAR-α) gen

• RAR-α gene product is a nuclear recenhancer in myeloid differentiation w

• in t(15;17), part of RAR-α gene on 17another gene, PML

• PML is normally a tumor suppressoractivation and promotes apoptosis

• the fusion gene product (pml-rarα) oto differentiate and blocks apoptosis

c Leukemia t(15;17)( )

ne on 17q in normal cells

eptor protein acting as transcription when bound to retinoic acid

q is translocated to 15q and fused to

r gene which modulates transcriptional

f APL causes failure of promyelocytes s

Retinoic acRetinoic acremission

• marrow hypoplasia not mli t l t• malignant clone matures

• leukemic clone replaced b• t(15;17) no longer readily • ‘differentiating agent’• relapse occurs, necessita

cid inducescid induces ns in APL

mandatoryt PMNto PMNby normal cells in marrowdetected

ating chemotherapy

Tumor-suppr

• inactivation of both alleles e.g., p53

minor DNA damagmajor DNA damag

e.g., retinoblastoma gene modulates cell cyc

• ? deleted in therapy-relatedpy

ressor genes

of gene allows tumor growth

ge - promotes repairge - promotes apoptosis

cling

d acute leukemia

Erythroid progenitor

Hemato-poietic

p oge to

Megakaryocytit

Lympho

Stem Cell progenitor

Lympho-hematopoieticStem Cell

GranulocyteMonocyte progenitorprogenitor

LymphoidStem Cell

T-cell progenit

B-cell progeni

RBC’s

te platelets

basophilsbaso-progenitor

neutrophil-progenitor

eosinophils

neutrophils

eo-progenitor

neutrophil progenitor

monocyte-progenitor

neutrophils

monocytes

tor T-cells

itor B-cells

Lineage & Stage

Acute lymphocytic le

• usually arises in early pr• B:T 4:1• occasional mixed B and

ti li tsuggesting malignant evlymphoid progenitor cell

Specificity in ALL

eukemia

rogenitor B or T cell

T cell phenotype, t t li lti t tvent at earlier multipotent

l

F t AFeature A

usual age group chi

myeloperoxidasestain

Auer rods

terminaltransferase ( TdT)

cell surface Ag’s B g

Ig or T cellreceptor generearrangement

ALL ANLLALL ANLL

ldren adults

- +

- ++ -

or T myeloidy

+ -

Flow cytometry in acute monocytic leukemia

Acute Le

Event Consequences

M t iMarrowfailure

neutropeniaanemia↓ platelets

Hyper-uricemia

tubular damage

DIC ↓ plateletsabnormal clotting

eukemia

i f tiinfectionweakness, fatiguebleeding

acute renal failure

bleeding

Acute Le

Organ infiltrationmarrow involveme

bone painenlarged liver, splg , phypertrophied gummeningeal infiltratg

headache, cran

eukemia

ent

een, nodes,mstionial nn. palsies

Acute Le

• blast leukocytosis

• leukostasis in smaltachypneaypdyspneatinnituslethargystuporstupor

eukemia

ll blood vessels:

Acute Leukem

• intensive combinat• chemotherapy cont• central nervous sys• bone marrow trans

patientspatients• therapy is dangero• supportive measuresupportive measure

– allopurinol– rbc and platelet transfu

antimicrobials– antimicrobials

mia - treatment

tion therapytinued beyond remissionstem prophylaxis (ALL)plantation in selected

useses

sions

NEJM 2008; 358: 274

A k iAcute Leukemia - re

AA

c h i l d re n

completeremission

90%remission

mediansurvival

6+ yrssurvival

5 yr disease-free survival

70%free survival

l fesults of treatment

ALL ANLLALL ANLL

n a d u l t s a d u l t s

75% 65%

1-2 yrs 1-2 yrs

20-45% 10-20%