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Isolated Monocytosis Was the Flag Preceding Abnormalities in Other Precision and Future Medicine 2019;3(1):30-35 CASE https://doi.org/10.23838/pfm.2019.00023 REPORT pISSN: 2508-7940 · eISSN: 2508-7959 Isolated monocytosis was the flag preceding abnormalities in other parameters of complete blood counts in chronic myeloid leukemia with e1a2 (minor, P190) BCR-ABL1 chimeric transcripts 1 1 1 1 2 Jae Won Yun1 , Jung Yoon , Jong Won Kim , Sun-Hee Kim , Chul Won Jung , Hee-Jin Kim 1 DepartmentofLaboratoryMedicineandGenetics,SamsungMedicalCenter,SungkyunkwanUniversitySchoolofMedicine, Seoul,Korea 2 DivisionofHematology-Oncology,DepartmentofMedicine,SamsungMedicalCenter,SungkyunkwanUniversitySchoolof Medicine,Seoul,Korea Received: March 14, 2019 Revised: March 18, 2019 Accepted: March 21, 2019 ABSTRACT Chronicmyeloidleukemia(CML)isamyeloproliferativeneoplasmwiththemolecular Corresponding author: Hee-Jin Kim hallmarkofBCR-ABL1 chimerictranscriptsfromt(9;22)(q24;q22).Inmorethan95%of Department of Laboratory CML,thefusionoccursinthemajorbreakpointclusterregion(M-bcr)ofBCR,mostcom- Medicine and Genetics, monlyproducingthee14a2ore13a2type.CMLwithe1a2BCR-ABL1byfusioninminor Samsung Medical Center, bcrisrare,accountingforapproximately1%ofCML.CMLwithe1a2BCR-ABL1isreport- Sungkyunkwan University edlyassociatedwithmonocytosisandpoorprognosis.Herewedescribeawomanwho School of Medicine, 81 Irwon- underwentbonemarrow(BM)studywithanimpressionofchronicmyelomonocytic ro, Gangnam-gu, Seoul 06351, leukemiabasedonthrombocytosisandprominentmonocytosis.Geneticworkupre- Korea vealed,however,t(9;22)ande1a2BCR-ABL1,whichindicatedCMLandexplainedher Tel: +82-2-3410-2746 unusualmonocytosis.Areviewofserialcompletebloodcounts(CBC)beforetheBM E-mail: [email protected] studydemonstratedthatisolatedmonocytosisprecededtheabnormalitiesinotherpa- rametersofCBC.Thepatientisonfollow-upwithtyrosinekinaseinhibitor(TKI,dasati- nib)medication.Closemonitoringisrequiredduetotheassociationofe1a2BCR-ABL1 withpoorresponsetoTKIandfrequentdiseaseprogression.Timelygeneticworkup anddeterminationoftheprecisetypeofBCR-ABL1transcriptsarecriticalforthediag- nosisandstratificationofthisraresubtypeofCMLwithdistinctgenotype-phenotype correlations. Keywords: e1a2BCR-ABL1;Leukemia,myelogenous,chronic,BCR-ABLpositive;Mono- cytosis This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// INTRODUCTION creativecommons.org/licenses/ by-nc/4.0/). Chronicmyeloidleukemia(CML)isoneofthediseaseentitiesincludedinmyeloproliferative 30 Copyright © 2019 Sungkyunkwan University School of Medicine JaeWonYun,etal. neoplasms(MPNs)bythe‘WHOclassificationoftumoursof t(9;22)/e1a2BCR-ABL1transcripts. haematopoieticandlymphoidtissues’[1].TheBCR-ABL1chi- merictranscriptsfromthechromosomaltranslocationt(9;22) CASE REPORT (q34.1;q11.2)isthemolecularhallmarkofCMLandisthe therapeutictargetoftyrosinekinaseinhibitors(TKIs)[2].De- A68-year-oldwoman wasreferredtotheDivisionofHema- pendingonthebreakpointswithinthebreakpointclusterre- tology-OncologyofSamsungMedicalCenterbecauseofper- giongene(BCR)on22q11andtheAbelsonmurineleukemia sistentthrombocytosis.Shehadbeenonfollow-upforhypo- viraloncogenehomolog1gene(ABL1)on9q34,variousforms thyroidism.Thecompletebloodcounts(CBC)atreferral offusiontranscriptshavebeenidentified[3].Inparticular, showedleukocytosisandthrombocytosiswithhemoglobin 9 threerepresentativebcrhavebeendescribedintheBCR (Hb)136g/L,whitebloodcell(WBC)19.470×10 /L,and 9 gene:themajorbcr(M-bcr;theareabetweenexons12–16), platelets737×10 /L(Table1).ThedifferentialcountsofWBC theminorbcr(m-bcr;betweenexons1–2),andthemicrobcr werebandneutrophils1%,neutrophils56%,eosinophils1%, (μ-bcr;betweenexons17–20).Morethan95%ofCMLcases basophils4%,lymphocytes15%,andmonocytes23%(abso- 9 andapproximatelyhalfthecaseswithacutelymphoblastic lutemonocytecount[AMC],4.478×10 /L)(Fig.1A).Neutro- leukemiawitht(9;22)haveBCR-ABL1transcriptsfromthere- philsdidnotshowdefinitedysplasia.Theresultsfrombio- arrangementatM-bcr,mostlythee14a2(orb3a2)ore13a2(or chemicalanalysiswerenormal.Bonemarrow(BM)study b2a2)types,producinga210-kDachimericprotein(P210). andrelatedtestswereperformedwithwritteninformedcon- BCR-ABL1transcriptsfromm-bcrproducea190-kDachimeric sentfromthepatientandrevealedhypercellularBMwith protein(P190),withthee1a2typebeingthemostcommon. 80%cellularitywithincreasedgranulopoiesis(withoutdys- Thee1a2typeBCR-ABL1isfrequentlydetectedatlowlevels plasia)andmegakaryopoiesiswithdysplasia(megakaryo- inCMLwithe14a2ore13a2typeBCR-ABL1[4].However,e1a2 cyteswithseparatenucleiandmononuclearforms)(Fig.1B, BCR-ABL1withoutothertranscripttypesisrareinCML,ac- C).Blastswerecounted4%ontheaspiratesmear.Onthe countingforapproximately1%ofcases[5-9].BCR-ABL1tran- otherhand,theCD34immunostainonthebiopsysection + scripts(e19a2)fromμ-bcrproducea230-kDachimericpro- showed5%to10%CD34 blasts(Fig.1D).Conventionalchro- tein(P230)andarealsorare.Interestingly,recentstudies mosomeanalysisusingBMcellsrevealed46,XX,t(9;22) havereportedthatthetypeofBCR-ABL1transcriptsaffects (q34.1;q11.2)(20)(Fig.2A),andfluorescenceinsituhybridiza- thediseasephenotypeandoutcome[10,11].Inparticular, tion(FISH)usingVysisLSIBCR/ABLDualColor,DualFusion e1a2BCR-ABL1havebeenreportedtobeassociatedwith TranslocationProbe(AbbottMolecular,DesPlaines,IL,USA) prominentmonocytosis,minimalbasophilia,poorresponse showedBCRandABL1generearrangementin99%ofinter- toTKI,higherratesofdiseaseprogressiontoaccelerated/ phasenuclei:nucish9q34.1(ABL1x3),22q11.2(BCRx3)(ABL1 blastphases,andpoorsurvival[5-9].Inthisreport,wedescribe conBCRx2)(198/200)(Fig.2B).Multiplexreversetranscriptase apatientwhohadprominentmonocytosismimickingchron- polymerasechainreaction(PCR)usingHemaVision-28N icmyelomonocyticleukemia(CMML)butwasdiagnosedas (DNADiagnostic,Risskov,Denmark)showedminor(P190) havingCMLafterthegeneticworkupthatdemonstrated BCR-ABL1transcriptsofthee1a2type(Fig.2C).Major(P210) Table 1. Serial complete blood counts in the patient a) b) Parameter Nov 11, 2015 Nov 28, 2016 Dec 6, 2017 Dec 4, 2018 Jan 18, 2019 Feb 28, 2019 Hemoglobin(g/L) 141 136 125 124 135 106 9 c) c) c) WBC(×10 /L) 5.380 6.94 9.830 14.770 19.470 2.59 9 c) c) c) Platelets(×10 /L) 236 250 386 602 737 79 9 c) c) ANC(×10 /L) 2.948 3.69 5.71 8.860 10.903 1.04 9 c) c) c) c) AMC(×10 /L) 0.462 1.048 2.035 2.363 4.478 285 c) c) c) c) c) Monocytes(%) 8.6 15.1 20.7 16 23 11 9 9 9 9 Localreferenceranges:WBC<8.630×10 /L,platelets<347×10 /L,ANC<8.300×10 /L,AMC<0.690×10 /L,andmonocytes(%)<8%. WBC,whitebloodcell;ANC,absoluteneutrophilcount;AMC,absolutemonocytecount. a) b) c) Atbonemarrowstudy; After4weeksofdasatinibmedication; Leukocytosis,thrombocytosis,andmonocytosis. https://doi.org/10.23838/pfm.2019.00023 31 e1a2BCR-ABL1chimerictranscriptinCML A B C D Fig. 1. (A) The peripheral blood smear of the patient showed leukocytosis with prominent monocytosis (red arrows), basophilia (red 9 9 arrowhead) (white blood cell, 19.470×10 /L with monocytes 23% and basophils 4%), and thrombocytosis (platelets 737×10 /L; Wright- Giemsa, ×1,000). (B) Bone marrow study revealed increased granulocytic precursors and dysplastic megakaryocytes (red arrows) on aspirate smear (Wright-Giemsa, ×400) and (C) increased cellularity (80%) in biopsy section (H&E stain, ×200). (D) CD34 immunostain on biopsy section showed increased CD34-positive cells (>5%; ×200). 6 BCR/ABL1transcripts(includinge14a2ore13a2types)ormi- satinibmedication(100mgdaily)showedHb10 g/L,WBC 9 9 cro(P230)BCR-ABL1transcripts(includinge19a2)werenot 2.590×10 /L,andplatelets79×10 /L. detected.SangersequencingoftheBCR-ABL1transcriptsin thepatientconfirmedthejunctionwithin-framefusionof DISCUSSION exon1ofBCRandexon2ofABL1,withoutadditionalnucleo- tidechanges(primersequencesavailableuponrequest)(Fig. AccordingtothecurrentWorldHealthOrganizationclassifica- 2D).MoleculargenetictestsfordrivergenemutationsinMPN tionofhematologicmalignancies,therearethreemajordis- (JAK2V617F,JAK2exon12,MPLexon10,andCALRexon9 easecategoriesinmyeloidneoplasmsotherthanacutemy- mutations)wereperformedusingperipheralbloodleuko- eloidleukemia:MPN,MPN/myelodysplasticsyndrome(MDS), cytesandwereallnegative.Collectively,shewasdiagnosed andMDS[1].TheMPNcategoryincludesCML(BCR-ABL1-pos- withCML,BCR-ABL1-positive,inchronicphase.Areviewof itive),chronicneutrophilicleukemia(CNL),polycythemia serialCBCbeforetheBMstudydemonstratedthatisolated vera(PV),andprimarymyelofibrosis(PMF).MPN/MDSin- monocytosisprecededtheabnormalitiesinotherparame- cludesCMMLandatypicalCML(BCR-ABL1-negative).Thedi- tersofCBC(Table1).Thefollow-upCBCafter4weeksofda- agnosticcriteriaforeachdiseaseentityincludesthepresence 32 http://pfmjournal.org JaeWonYun,etal. A B C D Fig. 2. (A) Conventional cytogenetic analysis revealed t(9;22) without additional cytogenetic aberrations (red arrows). (B) Fluorescence in situ hybridization study showed two fusion signals from BCR-ABL1 rearrangement (red arrowheads) generated by rearrangement of the breakpoint cluster region (BCR) gene on 22q11 and the Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene on 9q34 in 99% interphase nuclei. Note the nucleus with two normal (non-rearranged) copies of BCR and ABL1 genes (two green and two red signals, respectively; light- blue arrowhead). (C) Multiplex reverse transcriptase polymerase chain reaction using the HemaVision kit revealed minor BCR-ABL1 fusion transcript (P190) with approximately 320 bp size, indicating e1a2 type, on the M8F panel (right lane, red arrowhead). No amplicons were detected in the middle lane (M6B) for major BCR-ABL1 transcripts, including e14a2 (b3a2) and e13a2 (b2a2) types
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