CMLBIOLOGYFORTHECLINICIAN

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MEDI CAL ONCOLOGY
CMLbiologyfortheclinician
in2011:siximpossiblethings
tobelievebeforebreakfaston
thewaytocure
B.LeberMDCM
represents the most important advance in clinical
oncologyinthelastdecadenotonlybecauseofthe
magnitudeofthedifference(amorethan40%increase
in5yearsurvivaloverthatwithpreviouslyavailable
therapies)
1
,butalsobecauseofthemeansbywhich
thatincreaseoccurred.Inthissense,CMLrepresents
amodeldiseaseforoncology,withthePhiladelphia
chromosome being the frst chromosomal transloca
tion (and thereIore genetic deIect) identifable in any
human cancer
2
; the frst human Iusion-activated
oncogene, by identifcation oI Bcr-Abl as the translo
cationproduct
3
; the frst cancer treated with targeted
smallmoleculetherapy(imatinib,beginningin1999)
and the frst disease in which a gene-based test to
monitor disease bulk became a standard of clinical
practice
1
.Othertyrosinekinaseinhibitors(TKIs)that
aremorepotentagainstBcrAblarenowavailableor
indevelopment.
Furthermore,theapparentlongtermpersistence
ofdiseaseformanyyearsdespiteexcellentcontrol
representsthemostobviousclinicalcorrelateofthe
currentlydominant,butstillcontroversial,modelof
cancerstemcellbiology,whoseexplanationforthat
persistenceisthefactthatthetargetedtherapyhits
thedifferentiatedprogenyoftheCMLstemcell,which
itself is immune to that therapy. Despite the many
hidden biological and biochemical cellular com
plexities,theconceptualsimplicityofthatmodelis
pedagogicallypleasingandcaneasilybepresentedto
nononcologycolleagues,medicalstudents,patients
andtheirfamilies,andthemassmedia.However,as
theEnglisheconomistJohnMaynardKeynesnoted,
weareallprisonersofourimplicitmetaphysics,and
cliniciansareprisonersofthemodelstheycarryin
theirheadsofthediseasesthattheytreat.
The present article therefore examines several
featuresofthatmodelandpointsoutwherethecurrent
understanding of the cell biology and biochemistry
ofCMLandBcrAblindicatethatpartsofthemodel
may be oversimplifed or even wrong. Each oI the
newinsightshasimplicationsfortheprognosisand
therapyofCML(and,byextension,othermalignancies).
ABSTRACT
Chronicmyeloidleukemia(CML)isamodeldiseasein
oncology: it is the frst human cancer linked to a distinct
chromosomalabnormality,ultimatelycausingconstitu
tiveoveractivityofaknownoncogenictyrosinekinase
that represents a drug target. The introduction of the
tyrosinekinaseinhibitorimatinibintoclinicalpractice
hasfarexceededexpectationsandresurrectedhopethat
thefundamentalinsightsfromthewaroncancercan
lead to signifcant therapeutic advances. Nevertheless,
thecurrentperceptionamongcliniciansisthatimatinib
anditsnewermorepotentcousinsoffersuperblongterm
diseasecontrolformostpatients,butthatcurewithout
transplantationhasremainedelusive.However,several
important laboratorybased observations over the last
few years have changed those perceptions. Several of
thosedevelopmentsarediscussedhere,includingdirect
manipulationoftheapoptosispathwayincancercells
and prevention of disease progression with the use of
antioxidants. Intriguing results from a French study
indicate that, if disease progression is halted, a small
but signifcant group oI patients may be able to stop
imatinib therapy without disease recurrence. And for
patientswhosedisease,becauseofresistantstemcells,
needsamoredirectattackthantyrosinekinaseinhibitors
alone,severalapproachesinvestigatedinlaboratoryand
animalmodelsseempromising,andsomeareripefor
clinicaltesting,includinginhibitorsofSmoothenedand
5lipoxygenase, and suppression of autophagy. Thus,
there is realistic hope that true cure of CML, without
transplantation,maybeafeasiblegoalinthenearfuture.
KEY WORDS
Leukemia, stem cells, targeted therapy, tyrosine
kinaseinhibitor,apoptosis
1. INTRODUCTION
Theimprovementinclinicaloutcomefortreatedpa
tientswithchronicmyeloidleukemia(CML)arguably
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Therefore,inthespiritoftheQueenofHearts,who
toldAlicethatsheneededtobelievesiximpossible
things before breakfast, many recently investigated
features of CML biology are reviewed here with the
aimofdiscoveringwherethesciencestandsin2011.
Thisbriefreviewisnotintendedtobeexhaustiveor
completebutitwillfocusonrecentresultsthatmay
haveneartermclinicalapplicationbecausetheyin
volveagentsorapproachesthatarecurrentlyavailable
orwillsoonbeundergoingclinicaltrial.Dependingon
thereadersdegreeofadherencetothecurrentmodel
of CML pathophysiology and treatment, the number
of surprises presented may or may not exceed the
Queensquotaofsix.
2. SHUTTING DOWN KINASE ACTIVITY
COMPLETELY: IS IT NECESSARY?
Initialcharacterizationoftheconsequencesforcell
biologyoftheBCRABLfusiononcogeneledtothe
conceptuallypleasingnotionthattheBcrAblprod
uct functioned as an autonomously active protein
mimicking constant growthfactor signalling to
activatemanydownstreampathways,includingthe
wellcharacterizedRaspathway.Clinicianswerethus
presented with an easily identifable phenotype that
usedgrowthfactorstodriveupwhitecellnumbers.
A constitutively active growth factor mimic as a
downstream mediator would cause cell numbers
torapidlyandpersistentlyincrease.Inhibitingthat
effectwithTKIssuchasimatinibwouldreversethe
phenotype,butthediseasewouldremain.
However,itisnowclearthatBcrAblisanodefor
manydifferentsignallingpathwaysinhematopoietic
cells,andthatthosepathwaysnotonlymediateprolif
eration,butalsoalteredadherencetostromaandinhibi
tionofprogrammedcelldeath(apoptosis).Itisthislatter
importantnotionthathasmostrecentlycometothefore,
withsurprisingresultsfromDr.NeilShahslab,where
thepharmacodynamiceffectsoflongactingimatinib
werecomparedwiththoseofshortactingdasatinib
4
.
TheoriginalclinicaldosingforallcurrentlyactiveTKIs
inCMLwasbasedontheassumptionthatcontinuous
inhibitionofBcrAblwasneededtopreventprolifera
tion.Itisnowclearthattherelevantgoalisprobablynot
preventionofproliferation(althoughitoccursasacon
sequence),butrathertheinductionofapoptosis.Recent
insightsfrombiologicmodelsoftheprocessindicate
that,afteravariablelagphase,apoptosisistriggeredas
anallornothingprocessinasinglecellonceathreshold
isreached,andthereforethethresholddoesnothaveto
bebreachedcontinuously
5
.Thisthresholdbreaching
occurswhenantiapoptoticproteinsoftheBcl2family
(suchasBcl2,BclXL,orMcl1)arepreventedfrom
bindingtotheproapoptoticBcl2familymembersBax
orBak,whicharethenfreetoselfassociateandform
poresintheoutermitochondrialmembrane
6
.Thislast
stepistheonethatmakestheirreversiblecommitment
tocelldeath.
The process that peels Bcl2/BclXL off Bax/
BakistheactivationofthethirdclassoftheBcl2
familyofproteins(calledBH3proteins),whichin
cludesBim,Bad,Bmf,tBid,andothers.TheseBH3
proteinsactassensorsforvarioustypesofcellstress,
suchasgrowthfactordeprivation,DNAdamage,loss
ofintercellularadherence,andmanyothers
6
.Thus
the role of growthfactor stimulationand fake
growthfactorstimulation(suchasBcrAbl!)that
worksthroughtheRasandphosphoinositide3kinase
pathwaysistokeepthoseproteinsabsentorinactive.
When kinase activity in the CML cell is switched
off with inhibitors such as imatinib or dasatinib,
several BH3 proteins are released or activated
7,8
.
Furthermore, a rapid shutoff by BcrAbl of con
stitutive phosphorylation of Stat5, which is a key
transcriptionalupregulatorofBclXL,alsooccurs
4
.
Thecombinedeffectisthereforetotipthebalancein
favouroffreedBaxtokillthecell,andDr.Shahs
work has demonstrated that it is the magnitude of
this downstream effect (resulting from a deep, but
potentiallybrief,kinaseinhibition)thatdetermines
thecellsfate
4
. Because the fnal decision to die is the
resultofatitratablebalancebetweenantiapoptotic
proteinssuchasBclXLandproapoptoticactivators
suchasBimandBad(abalanceadjustedbykinase
inhibition),anydirecttippingofthebalanceinfavour
ofthelatterwouldenhancetheeffectsofTKIs.
Thatbalanceisthetargetofanewlydeveloped
classofdrugsdesignedtobeBH3mimetics,some
of which, such as navitoclax
9
and obatoclax, are
already in phase I/II clinical trials in lymphoid
malignancies
10
.WorkwithCMLlikecelllinesand
patient samples, including putative CML CD34+
CD38progenitorcells,havedemonstratedmarked
synergyofTKIsandtheBH3mimeticsinvitro
11
,
suggesting a promising future for such clinical
combinationsinmarkedlyenhancingtheextentof
leukemiccellkill.
3. IS THE CML STEM CELL THAT DRIVES THE
DISEASE ISOLATED, PERPETUAL, AND
UNASSAILABLE?
Despitetheenormousclinicalandconceptualstrides
madebytheintroductionofTKItherapyinCML,the
currentclinicalconsensusisthatthesedrugsrepre
sent excellent ways to control, but not to cure, the
disease, because they do not affect the behaviour
of the stem cell in which the disease started and
thatrepresentsanongoingsourceofnewleukemic
cells, leading to indefnite disease persistence and
riskofprogressiondespitecontrol.Thenextstepis
thereforetoexaminethenatureandlikelihoodofthis
'indefnite control and then to ask whether cure, in
theconventionalsenseoftheword,iseverpossible
withouttransplantationthatis,withtheapplication
ofTKItherapybyitselforincombinationwithother
drugsthatenhancetheeffect.
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With respect to the nature oI indefnite control,
theinvaluable,wellcharacterizeddatabasefromthe
pivotal IRIS (International Randomized Interferon
VersusSTI571)trialofpatientswithCMLtreatedus
ingTKIsoverprolongedperiodsoftimehasindicated
adiminishinglikelihoodofprogressiontoblastcrisis
as time goes on
1
. The current model that best ex
plainsthesedataisthatprogressionactuallyhappens
inatargetpopulationthatisdifferentfrom,andmore
maturethan,theCMLstemcell.Incertaininstances
atleast,thecellulartargetforthetransformingevent
during myeloid blast crisis has been identifed as a
granulocytemacrophageprogenitor.Elegantwork
byCatrionaJamiesonhasindicatedthatthemediator
ofthistransformationistheacquisitionofunregulat
ed beta-catenin activity in this specifc cell type that
now makes it behave like a stem cell, with indefnite
selfrenewalcapacityandthedecreaseddifferentia
tionthatgivesitthemyeloidblastphenotype
12
.The
most recent work Irom her laboratory has identifed
apotentialmolecularmediatorofthisupregulation,
withaberrantsplicingofGSK3B,alossoffunction
mutationthatpreventsthephysiologicdegradation
ofbetacateninbytheproteosome
13
.Theultimate
causeofthisabnormalsplicingthatultimatelyleads
tomyeloidblastcrisisisstillunderinvestigation.It
is thought that the transformation itself is directly
or indirectly a result of mutagenesis mediated by
reactiveoxygenspecies(ROS)thatareaconsequence
of overactive kinase activity caused by BcrAbl.
ExperimentsatthelaboratoryofDr.TomasSkorski
showed that this ROSmediated mutagenesis is also
associated with defcient DNA repair that, together,
yield the genomic instability of untreated CML
14
.
Skorski and others also showed that inhibition of
kinaseactivitybyTKIsinhibitsROSgeneration,with
theclinicalconsequencethatmutagenesisshouldde
creaseinfrequency.Inaddition,astreatmentwithTKI
progresses,itistheoreticallypossiblethattheactual
targetpopulationinwhichatransformingmutation
suchasbetacateninactivationwouldleadtomyeloid
blastcrisis(granulocytemacrophageprogenitorfor
myeloid blast crisis, common lymphoid progenitor
forlymphoidblastcrisis)decreasestotheextentthat
the chance of it occurring within the individuals
lifetime would be vanishingly small. Therefore, in
a subpopulation oI patients, true indefnite disease
controlthatwouldbefunctionallyequivalenttocure
isapossibility,atleastwithongoingtherapy.How
ever,aspleasingasthatoutcomemaybeforatleast
aproportionofpatients,evidenceisnowincreasing
thatthecontroversialpropositionthatTKIs(plusor
minus other medications) may cure CML is now an
achievablereality.
Apowerfulcounterargumenttosuchoptimism
isfoundinamathematicalmodelfromtheHarvard
evolutionary dynamics group
15
. The data used to
test the model refected the decline in BCRABL
transcriptspreciselymeasuredinpatientsontheIRIS
trial.Themodelmakestheassumptionthatthesmall
stemcellfractionslowlyandcontinuouslyexpands
during treatment, even as the more differentiated
progeny that are readily detectible die. Because
their model fts the clinical IRISdata,theassumption
ofstemcellinvulnerabilitytoTKIswastakentobe
correctasdemonstrated.However,anothermath
ematicalmodelproposedbyagroupinLeipzig
16
fts
theIRISclinicaldatajustasclosely,butmakesother
assumptions:namely,thattheCMLstemcelloccupies
a specifc kinetic niche in a competitive Iashion and
thatthepreventionoftheexpansionofthisstemcell
poolbyTKIswillnotpermitittocontinuetocompete
forthatniche
16
.Asaclinicalconsequence,thislat
termodelpredictsthatprovidedamutationcausing
blast crisis or resistance to TKI does not develop
(asdiscussedearlier),theCMLstemcellpopulation
will just slowly peter out. When this model was
proposed,itwaslookedatwithgreatskepticismin
theclinicalcommunityhowever,morerecentdata
fromaselectgroupofpatientswithwellcontrolled
diseasewhohavestoppedtheirtherapyunderclose
monitoringhavegivenearlyindicationsthat,forat
least a proportion of patients, disease eradication
maybefeasible.Severalgroupsaretryingthisap
proach, with a French group being the largest and
havingthelongestfollowup
17
.Theirtrial,STIM(the
Stop Imatinib trial), has allowed patients who, by
themostsensitivemoleculartechniques,haveshown
no detectible disease for a 2year period to stop
therapy in conjunction with frequent monitoring.
Interestingly,theHarvardandtheGermanmodels
bothpredictedthatanyrelapseswouldoccurwithin
a period of approximately 6 months. However, in
approximately half the patients studied, it appears
thatthediseasehasnotrecurredovertimeintervals
varyingbetween6and24months.Theriskofrelapse
seemstobeslightlyincreasedinpatientswhodidnot
receiveinterferontherapybeforetheimatinib,butthe
proportions were not signifcantly diIIerent in these
twosubgroups,atleastatearlyanalysis,indicating
that,contrarytoearlierpreliminaryreportsfromthe
samegroup,priorinterferontherapyisnotrequired
for a diseasefree state to persist offtherapy
18
.
Longerterm followup on this intriguing trial is
anxiouslyawaited.
4. IF TKIs CANNOT CURE BY THEMSELVES,
CAN WE OFFER THEM HELP?
IflongterminhibitionofBcrAblbyeffectiveTKIs
stilldoesnotcurethedisease(evenifresistanceis
prevented and the direct downstream effects are
enhancedbyBH3mimetics),thesedrugsmaynev
ertheless be the backbone of combination therapy
when added to agents that specifcally target a CML
stemcellthatispotentiallyresistanttoTKIalone.Over
thepastfewyears,severalintriguingreportsinthe
literaturehaveindicatedadifferentialsusceptibility
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betweennormalstemcellsandCMLstemorprecursor
cellsinanimalmodelsorfrompatients.
On the one hand, tantalizing evidence from a
murineCMLtransplantmodelsuggeststhattheCML
stem cell may require a physical niche that is dif
ferentfromthatfornormalstemcellsandtherefore
therapeutically exploitable. Richard Van Ettens
groupdemonstratedbothwithantibodiesandwith
knockout mice that the cell adhesion molecule
CD44AisrequiredforengraftmentofamodelCML,
butnotforengraftmentofnormalbonemarrow
18
.
GiventhatantiCD44antibodiespotentiallycapable
ofexploitingthisdifferentialsensitivityarecurrently
in preclinical development, that groups discovery
mayrepresentanexcitingnewtherapeuticavenue
19
.
On the other hand, several groups have also
identifed intrinsic cellular Iactors that are required
forCMLinitiationorpropagationandthatmayalso
bedifferentiallyexpressedorrequiredinCMLstem
cellscomparedwithnormalstemcells.Oneofthe
newest results involves one of the oldest drugs. A
high-profle publication has delineated a complex
effect of interferon on normal stemcell prolifera
tion:promotionofcellcycleentrywithshortterm
administrationthatturnsintopreventionofcellcy
clingwithchronicadministration
20
.Thatpublication
did not study CML stem cells nevertheless, despite
uncertaintyabouttheexactmechanismortimingof
administration,theindependentactivityofinterferon
againstCMLhaspromptedatleastfournationaltrials
inEuropetoinvestigatethecombinationofinterferon
and imatinib in newly diagnosed patients. Getting
therightdosingscheduletoavoidtreatmentdelays
fortoxicityhasbeenabittricky,butthepreliminary
results seem to indicate that in patients who can
toleratetreatment,theresponseisdeeperandfaster.
Theseresultshavepromptednewertrialslookingat
lowerdose interferon to mop up the residual stem
cells after an imatinib induction, with the hope
thatthesequencewilleradicateCMLstemcells
21
.
Therearealsomanyindicationsthatcombina
tionsofTKIs with newer agents may lead to signifcant
advancesineliminatingCMLstemcells.Twoseparate
groups have demonstrated in murine models that
Hedgehogsignalingisrequiredforthemaintenance
andexpansionofstemcellspositiveforBcrAbl
22,23
.
Both of these elegant experiments used knockout
micetodemonstratethatthedownstreammediating
targetofHedgehog,Smoothened(SMO),isrequired
for the development of BcrAblinduced CML. The
SMOknockoutdidnotaffectnormalhematopoiesis,
andanexcitingextensionofthisworkbybothlabs
indicates that administration of the SMO inhibitor
cyclopamine inhibited growth both in the murine
modelsandinpatientsamplesfromlongterminvitro
cultures.Cyclopamineistootoxictobeadministered
asadrugtopatients,butseveralSMOinhibitorsare
alreadyadvancedinclinicaldevelopmentbecauseof
theinterestinthispathway,whichiscriticalforother
malignanciessuchasbasalcellcarcinomaandglio
blastoma.Thenewerdrugsalsoshowsynergywith
TKIsagainstCMLprogenitorcellsfrominvitropatient
cultures.Preliminaryindicationsarethatnomajor
safetyconcernsareconnectedwiththeseagents,and
socombinationtherapywithTKIsforselectedgroups
ofpatientsmaybefeasiblerelativelysoon.
Anotherpotentialintracellulartargetsusceptible
todrugtreatmenthasbeenrevealedbythelaboratory
oI Dr. Pandolfni
24
.Thisgroupsstudiesweremoti
vatedbytheobservationthatCMLpatientshadaworse
prognosiswithhigherexpressionofthenuclearfactor
PML,wellknowntohematologistsinthecontextofthe
PMLRARalphatranslocationinacutepromyelocytic
leukemia(APL).Usingpatientsamplesandamouse
model,theseworkersdemonstratedthatdegradation
ofPMLbyarsenictrioxideretardstheselfrenewalof
CMLstemcells.Becausearsenictrioxideiscurrently
inclinicaluseforthetreatmentofAPL, their fnding
mayrepresentachancetoaddaneasilytestableagent
toTKI.However,particularattentionwouldhaveto
bepaidtotoxicityofthecombination,becauseboth
agentscanprolongtheQTinterval.
Bothoftheforegoingapproachesuseatacticof
fnding diIIerentially expressed pathways in CMLstem
cellsthatarerequiredfortheirselfrenewalanother
tactic is to try to fnd something that enhances the
killingofTKIssuchthatCMLstemcellsareincluded,
aswiththeuseofBH3mimeticsalreadydescribed.
Excitingprogressalongthoselineshasbeenmade
as well. Recent investigations have demonstrated
that the autophagy pathway, a current hot topic in
cancercelldeath,isactivatedascellstrytosalvage
themselvesfromapoptosis.Whenbothpathwaysare
circumvented,regulatednecrosisoccurs,withrapid
celldeath.Thisescaperouteappearstoberelevant
inCMLprogenitorandstemcellsfrompatients,such
thatexposingthemtoimatinibcausedthemtoturnon
theautophagypathwayandachieveatleastsomecell
survival
25
.Incombinationwithimatinib,inhibition
ofautophagybychloroquine(acurrentlyavailable
drug) resulted in signifcantly increased cell death
evenifprimitiveandprogenitorcellswereotherwise
resistant to imatinib because of BCRABL point
mutations
25
!Aclinicaltrialusingthiscombination
oftherapyinpatientshavingagoodbutincomplete
preliminary response to imatinib alone is about to
startintheUnitedKingdom.
Asaclearindicationofthefactthatonenever
knows under which stone gold may be found, a
recentreporthasindicatedthat,inamousemodel,
the enzyme 5lipoxygenase, which is involved in
leukotriene biosynthesis, is a required pathway to
maintainCMLstemcells,butnotnecessarilynormal
stem cells
26
. A drug that specifcally targets this
enzymeiscurrentlyused(andiswelltolerated)in
thetreatmentofasthma,andsotestsofacombina
tiontherapydirectedattheCMLstemcellandBcrAbl
maybefeasibleandpractical.
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Finally, the laboratory of Dr. Tessa Holyoake
inGlasgowhaspioneeredextensiveinvestigations
intopotentialagentsthatcoulddirectlycausecell
death (rather than prevent selfpreventing self
renewal)inquiescentCML stem cells. She identifed
a compound previously investigated as a farnesyl
transferase inhibitor (FTI) as a novel therapeutic
agent.Theexperimentsdemonstrateddirectinduc
tionofapoptosisinCMLstemandprogenitorcells
frompatients,regardlessoftheirresponsivenessto
imatinibsynergywhenaddedtoimatinibandrela
tivelackoftoxicitywhentestedonnormalhemato
poieticstemcells
27
.Intriguingly,thoseeffectsdo
notrequiretheFTIactivity,becauseacloselyrelated
congenerthatisequallyactiveasanFTIlacksthose
effects,suggestingthatactivityagainstsomeother
target(whichmightstillrequireFTIasapartner)is
doingthejob
27,28
.Preliminaryevidenceindicates
thatthisnewcompoundworksbyupregulationof
proteinkinaseCbetaactivity,leadingtoapoptosis,
because inhibition of that activity abrogated the
effectofthenewdrug
28
.Workonidentifyingthe
relevanttargetandenhancingtheuniqueproperty
hasbeensomewhatslowedbecausethedrugspatent
hasmigratedfromonepharmaceuticalcompanyto
another,buthopesarehighthatapplicationswillbe
foundnotonlyagainstCML,butalsoagainstother
cancerstemcells.
5. SUMMARY
The novel and exciting avenues being pursued in
theattempttogetattheCMLstemcellaremany,if
thatcellcannotsimplybeexhaustedbylongterm
ongoingandeffectiveBcrAblinhibition.Although
all the experiments so far have been based on in
vitroormousemodels(orboth),themultiplepoints
ofattackgivehopethatatleastonewillbeeffec
tive,andthattruecureofCMLwithoutanallogeneic
transplantation is a realistic hope within the next
decade,ifnotsooner.
6. CONFLICT OF INTEREST DISCLOSURES
BLisamemberofthemedicaladvisoryboardsand
speakersbureausforNovartisCanadaandBristol
MyersSquibbCanada.
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Correspondence to: Brian Leber, Department of
Medicine, Juravinski Hospital and Cancer Centre,
711 Concession Street, Room B3147, Hamilton,
OntarioL8V1C3.
Email:leberb@mcmaster.ca