Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases.

0.72 MB·English

by  He, Xin

Heetal.JournalofHematology&Oncology2013,6:11
http://www.jhoonline.org/content/6/1/11
JOURNAL OF HEMATOLOGY
& ONCOLOGY
REVIEW Open Access
Different mutations of the human c-mpl gene
indicate distinct haematopoietic diseases
Xin He1†, Zhigang Chen2†, Yangyan Jiang3, Xi Qiu1 and Xiaoying Zhao1*
Abstract
The human c-mpl gene (MPL) plays an important role inthe development of megakaryocytesand platelets as well
as the self-renewal of haematopoietic stem cells. However, numerous MPL mutationshave been identified in
haematopoietic diseases. These mutationsalter the normal regulatory mechanisms and lead to autonomous
activation or signalling deficiencies. In this review, wesummarise 59 different MPL mutations and classify these
mutations into four different groups according to theassociated diseases and mutation rates. Using this
classification, we clearly distinguish four diverse types of MPLmutationsand obtain a deep understand of their
clinical significance.This will prove to be useful for both disease diagnosis and the design ofindividual therapy
regimens based onthe typeof MPL mutations.
Keywords: MPL,Mutations, Mechanism, Individual therapy, Haematopoietic diseases
Introduction However, various MPL mutations alter the normal regu-
The human c-mpl gene (MPL), a cellular homologue of latory mechanisms; some may cause a complete or partial
theoncogenev-mpl,belongstothehaematopoieticrecep- loss of CD110 function, thus leading to thrombocytopenia,
tor superfamily [1,2]. The protein encoded by MPL, whileothertypesofmutationsresultintheautonomousac-
CD110, is a 635-amino acid protein consisting of four tivation of CD110 and the development of thrombocytosis
functionaldomains: the putative signalpeptide, the extra- (SummarisedinFigure1).
cellular domain, the transmembrane domain and the
intracellular domain. These domains correspond to exon
SeveralMPLmutationshavebeenidentifiedin
1,exons2-9,exon10andexons11-12,respectively[3].
associationwithhaematopoieticdiseases
In the absence of the CD110 ligand, thrombopoietin
Since the first two heterozygous MPL point mutations
(TPO), the extracellular domain, transmembrane domain
were identified in congenital amegakaryocytic throm-
and an amphipathic motif, KWQFP, localised at the
bocytopenia (CAMT) in 1999, mutations in hereditary
transmembrane-cytoplasmic junction, retain CD110 in
thrombocythaemia (HT), myeloproliferative neoplasms
the inactive state [4-6]. When TPO binds to CD110,
(MPNs), refractory anaemia with ringed sideroblasts
CD110 is dimerised and the tyrosine kinases JAK2 and
associated with marked thrombocytosis (RARS-t) and
TYK2becomeactivated,whichinturntriggerstheactiva-
acute myeloid leukaemia (AML) have been identified
tionofdownstreampositivesignallingpathways,including
[22]. CAMT is a rare inherited disorder that presents
JAK-STAT/Crkl, SHP2-Bad, SHC-MAPK, and PLC-PKC
with thrombocytopenia at birth, which eventually pro-
[7-19].IthasbeensuggestedthatCD110andTPOplayan
gresses into pancytopenia without physical malforma-
importantroleinthedevelopmentofmegakaryocytesand
tions. MPL mutations associated with this disease are
platelets as well as the self-renewal of haematopoietic
autosomal, recessive germline mutations, which play a
stemcells[3,20,21].
decisive role in the course of the disease [23,24].
According to the data collected by Ballmaier et al.,
*Correspondence:[email protected] we calculated the mutation rate of the MPL gene to
†Equalcontributors reach as high as 91.8% (56 out of 61 CAMT patients
1DepartmentofHematology,theSecondAffiliatedHospital,Zhejiang for whom MPL sequencing revealed MPL mutations);
UniversitySchoolofMedicine,Hangzhou310009,China
Fulllistofauthorinformationisavailableattheendofthearticle no mutations other than those found in the MPL
©2013Heetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Heetal.JournalofHematology&Oncology2013,6:11 Page2of8
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Figure1Aschematicsummaryofthemechanismthatdifferentmutationsofhumanc-mplgene(MPL)bringaboutdistinctbiological
effects.Type1mutation:MPLmutationsfoundinCAMT.Type2mutation:MPL-S505N、K39N、P106LmutationsfoundinHT.Type3
mutation:MPL-W515LandW515KmutationsfoundinMPNs,RARS-tandAML.Type4mutation:MPL-W515A,W515R,W515-P518delinsKT,
Y591D,A519T,L510P,A506T,T487A,Y252H,S204P,S204F,IVS11/12andIVS10/11.
gene have been identified in CAMT patients [25]. ClassificationofMPLmutations
HT, a hereditary disease of thrombocythaemia, is the We reviewed relevant papers published from 1999 to
second disease that was shown to be associated with 2012 and found that 59 different MPL mutations have
MPL mutations. The MPL mutations detected in HT been reported. According to the frequency of MPL
patients, S505N, K39N and P106L, are also germline mutations and the associated clinical conditions, such as
mutations. These mutations are inherited in a number inheritance pattern, diagnosis, clinical manifestation and
of ways: autosomal dominant inheritance, autosomal laboratory results, we categorised these mutations into
dominant inheritance with incomplete penetrance and fourdifferentgroupsasfollows (summarisedinTable 1):
autosomal recessive inheritance with possible mild
heterozygote manifestation, respectively. Various soma- Type1. MPLmutationsfound inCAMT;
tic mutations, such as MPL-W515L, W515K, W515A, Type2.MPL-S505N, K39N andP106Lmutations
W515R, and W515-P518delinsKT, have also been found inHT;
detected in MPN samples, such as polycythaemia vera Type3.MPL-W515L and W515K mutations found in
(PV),primarymyelofibrosis(PMF)andessentialthrombo- MPNs,RARS-tandAML;
cythaemia (ET), which manifest as the overproduction of Type4.OtherMPL mutations:MPL-W515A,W515R,
oneormoremyeloidlineages. W515-P518delinsKT, Y591D, A519T, L510P, A506T,
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Table1ClassficationandclinicalfeaturesofMPLmutationsindentifiedinhematopoieticdiseases
Mutationtype MutationandInheritancepattern Effect clinical Disease(mutationrate) Reference
manifestation
Type141 AutosomalrecessiveGermlinemutation Completelylose Thrombocytopenia CAMT(about91.8%) (25-30)
differentMPL orsignificantly
mutationsin reduceMPL
CAMT function
Type2S505N AutosomaldominantGermlinemutation, Autonomous Thrombocytosis HT(about54.5%) (22,24,34,35)
raresomaticmutation activateMPL
function
K39N,P106L Autosomaldominantwithincomplete Reducebinding Thrombocytosis HT(7%ofAfrican-American (40,41)
penetranceandautosomalrecessivewith affinityto individualsand6%ofArab
possiblemildheterozygotemanifestation ligand individuals)
germlinemutation thrombopoietin
Type3W515L/K Somaticmutation Autonomous Thrombocytosis MPNs(about1%inETand5% (48-50,57,59,
activateMPL inPMF,rareinPV),AMKL 66-69)
function withmyelofibrosis(about
25%),rareinRARS-t
Type4W515A/R, Somaticmutation Autonomous Thrombocytosis RareinMPNs、AMKLandET (52,57,59,70,71)
T487A,Y252H activateMPL respectively
function
A519T,L510Pand Somaticmutation Nofunctionor Unknown RareinPMF (57)
A506T mayberegulate
othergenetic
events.
W515- Somaticmutation Unclear Unknown RareinMPNs (72-74)
P518delinsKT,
Y591D,S204P/F,
IVS11/12andIVS
10/11
T487A, Y252H, S204P, S204F, IVS 11/12 and CAMTIIdisplaysalessaggressivecoursewithatransi-
IVS 10/11. ent increase in platelet counts during the first year and
delayed or no progression of pancytopenia. Additionally,
MPLmutationsfoundinCAMT types of missense and splice site MPL mutations, such as
Currently,41differentMPLmutationshavebeendetected the most frequent mutation, c.305G>C, are closely asso-
in CAMTsamples [25]. They can be classified into non- ciated with CAMT II. This is because these mutations
sense mutations, deletionsand frameshiftmutations, mis- cause amino acid changes or mRNA splicing defects in
sense mutations andsplice site mutations.Ballmaier et al. CD110,whichdonotcompletelyabrogatethefunctionof
analysed 9 patients with CAMTand found that the types CD110butleaveresidualactivity[28-30].Twolinesofevi-
of MPL mutations correlated with the clinical course of dence support this hypothesis:1.TPO-driven signallingis
the disease [26]. King then proposed a new classification significantlyreducedbutnoteliminatedinK562cellswith
of CAMT, type I and type II, based on the course of the missense mutations in in vitro assays [29] and 2. Colony-
diseaseandthetypesofMPLmutations[27]. forming cells derived from CAMT II patients with mis-
CAMT type I is characterised by persistently low sensemutationsremainreactivetoTPO[28].
platelet counts and early progression to bone marrow In general, several studies have confirmed the genotype-
failure. Nonsense, deletions and frameshift MPL muta- phenotype correlation in CAMT [28,31,32]. However, as
tions, such as MPL c.127C>T and c.378delT, may be few reports discuss the relationship between MPL muta-
responsible for this disease type, as these mutations tions and brain abnormalities, malignant transformation in
introduce premature stop codons and thus cause a CAMTisstillunclear[23,32,33].Duetothecausativefunc-
complete loss of CD110 function [28]. In in vitro assays, tion of MPL mutations, especially nonsense mutations, in
CD110 is not expressed in K562 cells with nonsense CAMT, gene therapy aimed to correct CD110 deficiency
mutations; therefore, no TPO-driven signalling can be seemspossible.
detected [29]. Colony assays have also revealed that the
total number of colony forming cells derived from MPL-S505N,K39N,andP106LmutationsassociatedwithHT
CAMT I patients with nonsense mutations was signifi- MPL-S505N is an activating mutation that was first
cantly reducedcomparedwith normaldonors[28]. detectedbyDingetal.inallmembersofaspecificJapanese
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familywithHT[22].TheyfoundthattheBa/F3cellstrans- observations may indicate ethnic specificity for these
fectedwiththemutanttype(S505N)butnotthewildtype two mutations. Both of these mutations are located
DNA survived, even without growth factor stimulation within the extracellular domain of CD110, which may
[22]. Additionally, a study has demonstrated the constitu- affect TPO binding, thereby leading to the defective
tive activation of downstream signals without factor de- clearance of TPO and thus causing thrombocythaemia.
pendenceinbothBa/F3cellswiththeS505Nmutationand However, whether the two mutations correlate with
platelets of the S505N mutant derived from HT patients complications, such as thrombosis or bleeding, requires
[22]. How does MPL-S505N induce ligand-independent additionalstatistical analysis ofthedata.
phosphorylation of downstream signalling molecules? At
leasttwomechanismshavebeenelucidated:1.MPL-S505N MPL-W515L/KassociatedwithMPNs,RARS-tandAML
transduces the signal via the autonomous dimerisation of The two mutations were independently assessed because
the MPL protein due to strong amino acid polarity [34] the most recent 2008 WHO diagnostic criteria for MPNs
and 2. MPL-S505N leads to movement of the transmem- highlightsthefunctionoftheMPL-W515L/Kmutationsin
brane domain and conformational changes, including tilt the diagnosis of ETand PMF [42]. This was the first time
and azimuthal rotational angles along the membrane axis, thatthesemutationsappearedinthediagnosticcriteria.
whichaltertheconformationofthenearbyintracellulardo- Although JAK2V617Fis the most common mutation in
mainandthusinduceconstitutivesignalactivation[35]. BCR-ABL-negative MPNs, approximately 50% of ETand
To elucidate the biologic profile of MPNs,Teofili et al. PMF patients are JAK2V617F-negative [43-47]. In 2006,
have assessed 38 children with PV and ET [36]. How- MPL-W515L was identified by Pikman et al., and MPL-
ever, when they conducted the MPL gene mutation a- W515K was discovered several months later [48,49]. The
nalysis, they identified MPL-S505N in 9 of 11 children frequencyratesofMPL-W515L/KinETandPMFpatients
with ET,thereby suggesting thatthese paediatriccasesof are approximately 1% and 5%, respectively, but they are
familial ET are in fact HT, which led them to question rarely found in PV patients [48,50]. Interestingly, the pro-
the revised WHO diagnostic criteria for ET. To evaluate portion of the MPL-W515L mutations is higher than that
this observation, they increased the number of children ofMPL-W515KmutationsinMPNpatients,althoughthe
in the study and still found erroneous diagnoses for chil- ratio of homozygous patients is lower for the MPL-
dren with ET [37]. Therefore, they proposed that to W515Lmutation[51-53].Thesemutationswereidentified
avoid erroneous diagnoses, the first step of the diagnos- not only in granulocytes but also in monocytes, B cells,T
tic screening should be to test for MPL-S505N in those cells, NK cells, and even haematopoietic stem cells
children with thrombocythaemia who had a familial his- [54-56]. However, increased mutation levels in the
tory [38]. Recently, the same group extended their study myeloid lineage combined with the observation that
to include 44 HT patients, including both children and MPN is a myeloproliferative rather than a lymphoproli-
adults, and found that 22 of the 44 patients (approxi- ferative disorder suggest a proliferative advantage toward
mately 54.5%) carried the MPL-S505N mutation. At the themyeloidseriesinducedbyMPL-W515mutations[54].
median follow-up of 9 years for the 22 patients with this The following aspects clearly indicate the close rela-
mutation, they observed thrombotic manifestation in 4 tionship between MPL-W515L/K mutations and the
cases, myocardial infarction in 7 cases, foetal loss in 2 pathogenesis of MPNs. 1. MPL-W515L/K mutations are
cases, deep vein thrombosis of the leg and Budd Chiari located in the unique amphipathic KWQFP motif of
syndrome in 2 cases, and splenomegaly and bone mar- CD110, which is important for preventing its spontan-
row fibrosis in almost all patients. Therefore, they con- eous activation [5]. Thus, MPL-W515L/K mutations
cluded that MPL-S505N was associated with clinical may cause spontaneous activation. In in vitro assays, se-
manifestations such as a significant thrombotic risk, veral signalling pathways were constitutively phosphory-
which, with age, evolved to splenomegaly and bone mar- lated and the S phase of the cell cycle was enhanced
row fibrosis, thereby noticeably affecting patient life in MPL-W515L/K-expressing cell lines; even when de-
expectancy [24]. Interestingly, most of the HT cases prived of cytokines, cytokine-independent colony forma-
reported with MPL-S505N were from Italian families; tion and higher megakaryocytic cloning efficiency have
Liuetal.havealsoobservedthisphenomenon,forwhich been reported [49,57]. In this process, the cytosolic tyro-
they argue that a founder effect in Italian pedigrees with sine 112 of CD110 MPL-W515 mutants is crucial and
HTmayexplain thisoccurrence[39]. represents a potential target for pharmacologic inhibition
MPL-K39N is a polymorphism restricted to African [58].2.Ininvivoassays,theanalysisoftumourigenesisin-
Americans, and approximately 7% of African Americans ductioncapacityofMPL-W515L/Kmutantsinnudemice
are heterozygous for this mutation [40]. In contrast, revealed a clinical phenomenon similar to that observed
MPL-P106L was found in approximately 6% of Arabic with ET and PMF and showed atypical megakaryocytic
individuals but not in Caucasian individuals [41]. These hyperplasia, splenomegaly and thrombocytosis [49,57,59].
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3. Currently, MPL-W515L/K mutations have not been inhibitors display therapeutic value for MPN patients with
observed in normal individuals, and several studies have MPL-W515L/K mutations [63-65]. These observations
indicated that MPN patients with MPL-W515L/K muta- confirmthestatusofMPL-W515L/KinMPNs.
tionspresentwitholderage,lowerhaemoglobinlevelsand The MPL-W515L mutation has also been identified in
higher platelet counts. However, the relationship between RARS-t and AML patient samples. Currently, RARS-t
mutation and complications, such as thrombosis, remains patients harbouring the MPL-W515L mutation are rare
unclear[51,53,60].4.TwoMPL-W515Lmutation-positive [66-68]. However, the mutation rate of MPL-W515L has
PMFpatientsweretreatedwithallogeneicstemcelltrans- beenfoundtobeashighas25%inacutemegakaryoblastic
plantation (allo)-SCT, and the MPL-W515L mutation was leukaemia(AMKL)withmyelofibrosis,whichisa subtype
not detected after allo-SCTand mutation status remained of AML [69]. The MPL-W515L mutation may also be
negative for a long follow-up period, which is in line with involved in the pathogenesis of RARS-t and AML; how-
the absence of clinical or molecular relapse [61]. This ob- ever, as reports on this topic are sparse, the function of
servationsuggeststhattheMPL-W515Lmutationcouldbe themutationinthesetwodiseasesremainsuncertain.
used as a minimal residual disease marker and shows that
MPL-W515L plays a pathogenic role in MPN. 5. As men- OtherMPLmutations
tioned above, MPL-W515L/K mutations may cause spon- Due to the extremely low mutation rate and unknown
taneous signal transduction, including that of the JAK- function of some mutations, we classified these muta-
STAT/Crklpathway.Moreover,varioussmallmoleculeJAK tions together into one group. Compared with the MPL-
kinase inhibitors not only inhibit spontaneous activation, W515L/K mutations, MPL-W515A/R mutations were
thereby reducing the colony-forming capacity of cells with found to be significantly less frequent [48,52,57]. How-
MPL-W515L/K mutation in in vitro assays, but also effec- ever, it is conceivable that MPL-W515A/R mutations
tively relieve the symptoms observed in a MPL-W515L function via a mechanism similar to that of the MPL-
murine model of MPN [59,62]. Additionally, JAK kinase W515L/K mutations, as they are mutations of the same
Figure2Aproposedstrategyformanagementofpatientswiththrombocytopeniaorthrombocytosis.
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amino acid. MPL-A519T, L510P and A506T mutations patientstestnegative,aType3mutationscreeningshould
are not gain-of-function mutations, and some scholars becarriedout.WhenpatientstestpositiveforType2and
have hypothesised that these mutations have no rele- TPO mutations, an HT diagnosis should be considered.
vance to haematological disease or may be regulators of However,whenpatientstestnegativeforType2andTPO
othergeneticevents[57].Incontrasttoothermutations, mutations, sporadic thrombocythaemia should be consi-
MPL-T487A was observed in an acute megakaryoblastic deredwhileadheringtothe2008WHO criteria[42].Per-
leukaemia (AMKL) patient and induces a myeloproli- haps in the near future, when a diagnosis of MPN
ferative disorder in mice by conferring the ability of according to the 2008 WHO criteria is possible, JAK2
cytokine-independent cell growth [70]. The recently inhibitors that are currently being assessed in trials may
detected MPL-Y252H mutation in ET also displays a beavailableforpatients.
growth-promotingeffect[71].However,thefunctionofthe Nevertheless, several questions regarding MPL muta-
MPL-Y591D,W515-P518delinsKT,S204P/F,IVS11/12and tions remain unresolved. Why does one mutation, such
IVS10/11mutationsremainsunknown[72-74]. as MPL-W515L, give rise to several disease phenotypes,
namely ET, PMF, RARS-T and AML? The MPL-S505N
mutation found in HT samples is a germline mutation;
Conclusions however, three acquired mutation cases were recently
In conclusion, several MPL mutations have been identi- reported for MPNs [53,57]. Is this a coincidental phe-
fied in association with haematopoietic diseases. These nomenon, and do other MPL mutations also possess this
mutations may alter the normal regulatory mechanisms property? Finally, do JAK kinase inhibitors also have
and lead to autonomous activation or signal deficiency. therapeutic potential for patients with MPL mutations,
In this review, we assessed 59 different MPL mutations such asMPL-S505N,thatalsocause signalactivation?
and classified these mutations into four different groups
based on the associated diseases and mutation rates. Abbreviations
MPL:Humanc-mplgene;CAMT:Congenitalamegakaryocytic
Using this classification, we clearly demonstrate the ex-
thrombocytopenia;HT:Hereditarythrombocythaemia;
istence of four diverse types of MPL mutations and their MPNs:Myeloproliferativeneoplasms;ET:Essentialthrombocythaemia;
clinical significance. Different types of MPL mutations PMF:Primarymyelofibrosis;PV:Polycythaemiavera;AMKL:Acute
megakaryoblasticleukaemia;RARS-t:Refractoryanaemiawithringed
induce distinct haematopoietic diseases, and the same
sideroblastsassociatedwithmarkedthrombocytosis.
haematopoietic diseases may be caused by different mu-
tations. Therefore, individual treatment regimens are Competinginterest
Theauthorsdeclarethattheyhavenoconflictofinterestrelatingtothe
required to intervene in haematopoietic disease based
publicationofthismanuscript.
on the type of mutation present. We proposed a strategy
for patients with thrombocytopenia or thrombocytosis, Authors’contributions
especially with a family history and congenital history YJandXQcontributedtodatapreparation.XH,ZCandXZwereinvolvedin
conceptdesign,datacollection,andmanuscriptpreparation.Allauthorsread
(Summarised in Figure 2). For example, for patients with
andapprovedthefinalmanuscript.
thrombocytopenia, excluding secondary causes (i.e.,
medicine, infection, connective tissue diseases, hypers- Acknowledgments
ThisworkwassupportedbytheNaturalScienceFoundationofZhejiang
plenism or aplastic anaemia), a screening for Type 1
province,China(GrantNo.2009c03012-4).
MPL mutations should be performed, especially for
patients with a congenital history. If a Type 1 mutation Authordetails
1DepartmentofHematology,theSecondAffiliatedHospital,Zhejiang
is present, a diagnosis of congenital amegakaryocytic
UniversitySchoolofMedicine,Hangzhou310009,China.2Departmentof
thrombocytopenia can be suggested and an appropriate Oncology,theSecondAffiliatedHospital,ZhejiangUniversitySchoolof
therapeutic schedule can be formulated, including trans- Medicine,Hangzhou310009,China.3UItrasonicDiagnosisDeparment,the
SecondAffiliatedHospital,ZhejiangUniversitySchoolofMedicine,Hangzhou
fusion, stem cell transplantation or even gene therapy in
310009,China.
the future. Otherwise, other congenital diseases should
be considered. For patients without a congenital history, Received:25November2012Accepted:22January2013
Published:25January2013
primary and exclusive diseases may be considered, such
as idiopathic thrombocytopenia purpura or other dis-
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