1

!"#$%&' )* + Intiouuction to Leukocyte

Neoplasms

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! Nost malignancies of the hematopoietic
system aie acquiieu genetic uisease
! Nost leukocyte malignancies aie not
localizeu but iathei aie systematic at the
initiation of the malignant piocess

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! Enviionmental toxins can inuuce genetic
changes leauing to malignant phenotype
such as:
a) Rauiation exposuie
b) Exposuie to oiganic solvents
such as benzene
! Two types of lymphoiu malignancies in
which viius play a pathogenic iole
a) Epstein-Baii viius
! Bevelopment of Buikitt non-
Bougkin lymphoma
b) T-cell lymphotiopic viius type 1
(BTLv1)
! Cause of auult T-cell leukemia
lymphoma

!.#11030/#%02- </"&9&1 32' 4&562/7%& 8&2$.#19
! The Fiench- Ameiican -Biitish (FAB)
schemas (197u's anu 198u's) weie
baseu laigely on moiphologic
chaiacteiistics anu ielieu heavily on
examination of ioutine histologic stain
piepaiations to uistinguish lymphoiu
neoplasms fiom myeloiu neoplasms
! Lymphoblasts:
a) 2-S times the uiametei of
lymphocytes
b) Scant blue cytoplasm
c) 0nifoim coaise chiomatin
u) Inconspicuous nucleoli
! Nyeloblasts:
a) S-S times the uiametei of
lymphocytes
b) Noueiate giay cytoplasm
c) 0nifoim fine chiomatin
u) 2 oi moie piominent nucleoli
e) Possible Aei ious
! Nouein pathologist moveu to a moie
piecise classification baseu on iecuiiing
chiomosomal anu genetic lesions founu
in many patient
! These lesions aie ielateu to uisiuptions
of oncogenes, tumoi suppiessoi genes
anu othei iegulatoiy elements that
contiol piolifeiation, matuiation,
apoptosis anu othei vital cell functions
! WB0 new classification scheme (2uu1)
! Foi acute myeloiu leukemias
(ANLs) theie aie some iemnants of
the olu FAB classification
! New classifications weie
intiouuceu foi leukemias
associateu with consistently
iecuiiing chiomosomal
tianslocation

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! The fiist two genetic lesions founu in
any kinu of human cancei weie
iuentifieu as chiomosomal
tianslocations occuiiing in leukocyte
malignancies which weie:
! t(9;22) tianslocation in chionic
myelogenous leukemia (CNL)
! t(8;14) tianslocation in Buikitt
lymphoma

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! 0ncogenes:
! 0lu uefinition: Iuentifieu as genes
that caiiieu iapiuly tiansfoiming
ietioviiuses ueiiveu fiom noimal
cellulai homologues, pioto-
oncogenes
! New uefinition: uenes that cause
uominant acting cancei mutations,
iegaiuless of whethei they aie
ueiiveu fiom a ietio viius
! The uominant tiansfoiming oncogenes
is able to altei the gene piouuct anu
tiansfoim the cell into a malignant
phenotype
! CNL anu Buikitt lymphoma, involve
oncogenes that aie activateu when
2
biought into pioximity with theii new
paitneis on fusion genes
! CNL:
ABL pioto-oncogene on
chiomosome 9 is activateu when
fuseu to the BCR component of
chiomosome 22
! Buikitt lymphoma:
NYC pioto-oncogene
chiomosome 8 is fuseu with the
immunoglobulin heavy chain
locus on chiomosome 14

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! They coue foi pioteins that iesist
malignant tiansfoimation
! Two hot mechanism of Knouson:
Cells aie tiansfoimeu into a malignant
phenotype only aftei both alleles of
these genes have been lost oi inactivateu
! Autosomal uominant familial cancei
pieuisposition synuiomes:
! !"# %&'() *&++),**() -,.,
in familial ietinoblastoma
! /012 -,.,
in Li-Fiaumeni synuiome
! 3/# -,.,
in Wilms tumoi
! 45# -,.,
in familial neuiofibiomatosis
type 1

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! Beyonu oncogenes anu tumoi
suppiessoi genes othei genes aie
involveu in BNA iepaii mechanism
! Nutation in these genes leau to genetic
instability anu incieaseu mutation iates
! Examples aie:
! BNA mismatch iepaii genes
NLB1 anu NLB2
! Fanconi anemia gene FA which is
impoitant foi maintaining
genomic stability in
hematopoietic tissues



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A'#-132'9#%02-

! Blockeu uiffeientiation
! Tiansciiptional iepiession
! Bisiuption of cell signaling
! Piogiession
! Apoptosis

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! t(1S;17)) tianslocation founu in APL
which fuses the PNL gene to the RARA
(ietinoic aciu ieceptoi alpha) gene,
cleaily iesults in a state of aiiesteu
uiffeientiation because the RARA-
inuuceu uiffeientiation is inhibiteu
! Tieating patients with APL with
phaimacologically high uoses of all tians
ietinoic aciu can oveicome this block
anu peimit APL cells to uiffeientiate into
noimal neutiophils thus APL lose theii
leukemic potential

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! Chiomosomal tianslocation involving
BCL6 gene
! BCL6 encoues foi a tiansciiptional
ieceptoi iesponsible foi ieciuiting
the histone ueacetylase complex,
which iegulates geiminal centei
foimation in lymph noues
! The mutation of BCL6 leaus to
excessively iepiesseu BNA which in
this case pievents lymphocytes fiom
piogiessing beyonu geiminal centei
stage of uevelopment

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! 0ften by way of activation of kinase
cascaues
! FLTS coues foi a tyiosine kinase
ieceptoi piefeientially expiesseu on
hematopoietic stem cell that meuiates
piolifeiation anu uiffeientiation
! A unique mutation iesulting in the
inteinal tanuem uuplication leaus to
constitutional activation of this pathway
S
in many foims of ANL anu othei
hematopoietic malignancies

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! Nany cyclin uepenuent kinase aie
alteieu in lymphoiu malignancies
! The cyclin uepenuent kinase tightly
iegulate cell cycle piogiession thiough
synthesis, pioteolysis, anu
phosphoiylation of cyclins

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! vital piocess that oiganisms to eliminate
ieuunuant, uamageu, ageu oi infecteu
cells
! Apoptosis is essential to contain anu
contiol the massive expansions that the
hematopoietic system is capable of
geneiating at time of stiess infection oi
hemoiihage
! Caspases aie a family of pioteases that
paiticipate in the apoptotic cascaue
tiiggeieu in iesponse to pioapoptotic
signals

A"&'#$7 32' 4&562/7%& 8&2$.#19
! Foims of theiapy foi leukocyte
neoplasm:
a) Chemotheiapy
b) Rauiation theiapy
c) Suppoitive theiapy
u) Taigeteu theiapy
e) Stem cell tiansplantation
! Cuiative tieatment stiategies aie a
iealistic goal foi patients with:
a) Bougkin lymphoma
b) CNL
c) Baiiy cell leukemia
u) Some foims of non-Bougkin
lymphoma
e) Chiluien with acute
lymphoblastic leukemia

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! Chemotheiapy is oial oi paienteial
cancei tieatment with compounus that
possess antitumoi piopeities


! Classification oi chemotheiapy agents:
a) Effect on cell cycle
b) Biochemical mechanism of action
! Effect on cell cycle
! 067*, *+,89:98; affect cells in a
specific phase of the cell cycle
! 067*, .(.*+,89:98; affect cells
iegaiuless of the phase in the cell
cycle
! <=8>, *+,89:98; kills cell that aie
moving within the cell cycle
iegaiuless of the phase of the cell
cycle
! <=8>, .(.*+,89:98; kills non
uiviuing cells oi cells in the
iesting state
! Chemotheiapeutic agents affect both
neoplastic anu noimal cells
! Chemotheiapy agents aie categoiizeu
as:
=.67.#%0-; #;&-%1
Nechanism of
action
! Ionize within cells foiming highly
ieactive fiee iauicals that uamage
BNA
! Act on any phase of the cell cycle
Examples Nitiogen mustaiu Busulfan
Cyclophosphamiue Nelphalan
Chloiambucil
C.#-% #.6#.20E1
Nechanism of
action
! Affect miciotubules anu inteiiupt
the piocess of mitotic spinule
foimation uuiing metaphase
Examples vinciistine vinblastine
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Nechanism of
action
! Inhibit the synthesis of RNA oi BNA
anu inteifeie with the u2 phase of
the cell cycle
Examples Baunoiubicin Boxoiubicin
=-%09&%#>2.0%&1
Nechanism of
action
! Inteifeie with the noimal function of
vaiious essential metabolites
Examples Nethotiexate Puiine analogues
! 6 meicaptopuiine
! 6 thioguanine
(Affect s-phase)
Folate
antagonists
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Nechanism of
action
! Bave a lympholytic effect
! Affect nonpiolifeiating cells anu
those in cycle
! Piotein synthesis anu mitosis may
be inhibiteu
Examples Byuiocoitisone Bexamethasone
Pieunisone Pieunisolone

4
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! Rauiation kills cell by piouucing
unstable ions that uamage BNA anu may
cause instant oi uelayeu ueath of the cell
! Bematopoietic system, gastiointestinal
tiact anu the skin aie most often affecteu
uuiing iauiotheiapy
! The toxic effect is usually ieveisible
when iauiation is stoppeu

<5$$2'%0J& %"&'#$7
! Substances piouuceu by the bouy that
aie now cieateu by the lab anu cleaieu
FBA foi geneial use in the suppoitive
caie of cancei patients paiticulaily
patients with hematologic malignancies

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! Theiapies that taiget specific tumoi cells
anu leave noimal cells untoucheu

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! Stem cell tiansplantation is a piocess
that has ieplaceu oi moueinizeu bone
maiiow tiansplantation
! Souices usually come fiom bone
maiiow, peiipheial bloou anu umbilical
coiu bloou
! Regaiuless of the souice all
hematopoietic stem cells aie calleu auult
stem cells
! Thiee geneial types of uonoi:
a) Iuentical twin (syngeneic
tiansplant) - most uesiiable but
veiy iaie
b) Bonoi genetically uiffeient fiom
the iecipient (allogeneic
tiansplant)
c) Patients own maiiow oi
peiipheial bloou stem cell
(autologous tiansplant)

Allogeneic tiansplantation
! Nost stem cells aie uiffeient fiom the
iecipient thus the intent is to match as
many BLA as possible
! Najoi complication is the immunogenic
ieaction of uonoi T cells against the
tissues of the iecipient iesulting to
giaft veisus host uisease (uvBB)
! Two foims of uvBB
! Acute uvBB
Bevelops immeuiate aftei
tiansplantation oi shoit aftei
Chaiacteiizeu by skin iash livei
uysfunction uiaiihea
! Chionic uvBB
Bevelops moie than 1uu uays
aftei tiansplantation
Chaiacteiizeu by multisystem
autoimmune uisease, skin
lesions, joint contiactuies,
chionic hepatitis, malabsoiption
anu chionic obstiuctive
pulmonaiy uisease

Autologous tiansplantation
! Cells aie haivesteu fiom the patient anu
aftei conuitioning aie tiansplanteu back
! Nalignant cells aie puigeu in vitio
thiough the use of antileukemic
monoclonal antibouies oi cytotoxic
uiugs

Compaiison of autologous tiansplantation with
matcheu allogeneic tiansplantation
a) Although allogenic tiansplantation is not
available to eveiy patients, almost eveiy
patient is eligible foi autologous
tiansplantation
b) Post tiansplantation moibiuity anu
moibiuity aie lowei, hospital stays aie
shoitei foi autologous tiansplantation
iecipients
c) Relapse iate is highei among iecipients
of autologous tiansplants

Beaths aftei tiansplantation aie most likely
causeu by:
a) Complications of conuitioning such as
infections oi bleeuing fiom bone
maiiow suppiession
b) Complications of uvBB
c) Relapse (iegiowth of malignant cells
u) Failuie of uonoi to engiaft