Posted on Authorea 12 May 2020 — CC-BY 4.0 — https://doi.org/10.22541/au.158931094.41451784 — This a preprint and has not been peer reviewed. Data may be preliminary. rtclo h ninCidodClaoaieLuei ru IiL) opiigo r-hs of pre-phase a of comprising (ICiCLe), Group BCP-ALL Leukemia (SR) Risk Collaborative Standard mg/m CD20, the Childhood on 60 for Indian initiated prednisolone aberrant negative was the with child were BCP-ALL of the of and which diagnosis protocol following working CD86; rendered, A cells). and was noted. expression 14% CD81 and Cytoplasmic not CD33 (dim; also CD79a markers. CD38, CD13 was associated cytoplasmic HLA-DR, expression megakaryocytic-lineage and (anti-MPO) & with CD34, cells) myeloperoxidase monocytic along 90% for markers, associated (bright; CD10 positive T-lineage CD33 dim also CD117, of were and expression positivity. blasts CD19 antigen myeloperoxidase bright The cross-lineage cytochemical showed was expressed There blasts blasts the CD22. the of cytometry, 2% flow rods; On Auer without cytoplasm hemoglobin basophilic The ( blasts margin). re- subcostal circulating x10 Examination left 14.0 62% the count duration. below platelet 1-week cm g/L, (2 of 46 splenomegaly pallor was and cm) and 11 fever (span therapy. with hepatomegaly steroid presented vealed child high-dose female of two-and-a-half-year-old week A one following subset blast myeloid History large Case a of emergence the showed but precursor B-cell of 1–3 being 4% and common B/myeloid (MPAL), most (BCP-ALL) leukaemia acute leukaemia mixed-phenotype lymphoblastic of 48% acute as many as in occur ZNF384 any in Introduction unreported leukemias among previously entity is emerging distinct It this of patients. with aware potential. ZNF384-rearranged be BCP-ALL differentiation in should multi-lineage as Hematologists previously also with therapy. or therapy now, CAR-T-cell corticosteroid leukemia following and pre-phase or acute after leukemias; ZNF384-re- relapse patient mixed-phenotype at re-arranged described therapy. KMT2A as phenomenon corticosteroid in rare either a mostly of present is 7-days switch to (BCP-ALL) Lineage following leukaemia recognized immunophenotype. blasts pro-B lymphoblastic increasingly myeloid acute are predominantly precursor leukemias to B-cell arranged lineage-switch standard-risk apparent re-arranged an TCF3-ZNF384 showed with girl 2-year-old A Abstract 2020 12, May 1 Rana Sonia Kapadia Alpeshkumar therapy. post-corticosteroid pre-phase leukaemia ZNF384-rearranged lymphoblastic a acute in precursor clone B-cell myeloid prominent a of Emergence otGaut nttt fMdclEuainadResearch and Education Medical of Institute Graduate Post erpr hlegn aewith case challenging a report We zn ne rti 8)r-ragmnsaercnl eonzdctgntcanraiisthat abnormalities cytogenetic recognized recently are re-arrangements 384) protein finger (zinc 1 rsatSharma Prashant , TCF3, 2 di he iie doses. divided three in /d i.1A-B Fig. 1 reehSreedharanunni Sreejesh , u also but 9 Ladttlluoyecut1. 10 x 14.7 count leucocyte total and /L 1 .Bn arwaprto eeld8%bat ihsat,agranular scanty, with blasts 82% revealed aspiration marrow Bone ). P0,EW1 A1,CEB,AI1,SYNRG ARID1B, CREBBP, TAF15, ESWR1, EP300, a pehSachdeva Updesh Man , TCF3-ZNF384 1 eea uinprnr of partners fusion Several . 4 1 eragmn htiiilypeetda BCP-ALL as presented initially that rearrangement 1 aa Muhammed Safal , 1 n mt Trehan Amita and , ZNF384 9 L eihrlbodfimshowed film blood Peripheral /L. 1 nrn Karmakar Indrani , aebe ecie,the described, been have 1 and BMP2K 1 , Posted on Authorea 12 May 2020 — CC-BY 4.0 — https://doi.org/10.22541/au.158931094.41451784 — This a preprint and has not been peer reviewed. Data may be preliminary. iwo bec fmtpae ute IHtsigwspromduigacmecal vial dual- available commercially of a rearrangement using confirmed performed that was Germany) testing GmbH, FISH (ZytoVision 1G) further probe metaphase, break-apart of colour absence the of revealed view testing FISH cytoplasmic report Repeat and initial negative that the CD15 The showed and BCP-ALL. CD36, reviewed blood of were CD14, immunophenotype results peripheral CD64, cytometry) initial ( on (flow the CD33, anti-MPO performed showed and (CD13, myeloperoxidase blasts cytometry antigens cytochemical 10% flow myeloid remaining Repeat expressed The blasts cy- myeloperoxidase. absent. unequivocal the were ( showed diagnosis of and cells blasts of 90% nucleoli the The prominent time of nuclei, rods. the 20% indented Auer at in with leukocyte without larger positivity her cytoplasm were myeloperoxidase basophilic well, blasts tochemical granular appeared these of diagnosis, clinically amount at toddler moderate morphology the the although to therapy, trast 63x10 steroid to pre-phase increased of count week one After PBX1 of presence revealed oyi el a onstwrsteoii fti ekmafo rmtv eaooei rcro with granu- precursor in hematopoietic primitive also a present from be leukemia to this shown of subsequently origin lie the and differentiation might towards divergent blasts explanation points for lymphoid may alternative the cells cells An in stem locytic leukaemia noted diagnosis. supported of initially at is plasticity This blasts translocation of unmasking inherent myeloperoxidase-positive blasts. the lymphoid 2% the represent preponderant simply of in the could by presence It outnumbered myeloid the case. initially large our by was of in that emergence therapy or sub-clone steroid myeloid myeloid high-dose to a of lymphoid week from one therapy switch following T-cell lineage clone receptor the antigen explain may chimeric mechanisms or Various agents CD19-targeting either mostly reported received being have leukemias, who pediatric in often more occurs leukemias It exceptionally, in (and with phenomenon. increase immunophenotype patients rare significant myeloid a in a to is leukemias with lymphoid acute 8, from in conversion day ) by i.e. increase switch, fivefold lineage A a showed outcome count unfavourable leukocyte relatively a total and the day-8 routine myeloblasts. at too, in steroids case frequent to our response are poor MPALs In counts, with literature leukocyte the dilemmas total meet higher in diagnostic not with well-documented Such did also MPAL. immunophenotype are of initial and diagnosis overall practice CD33 the for and/or but criteria myeloperoxidase, CD13 required expressed type of the blasts B/myeloid upregulation 2% MPAL, and About or immunophenotype) patient. BCP-ALL (pro-B as expression CD10 either dim present too these leukemias, ( 12p13 and TCF3-ZNF384 (Berlin-Frankfurt-Munster) to BFM prior augmented in prophylaxis. Discussion delay an course antifungal 2-week on her stormy a is continues to a patient and leading had the protocol drainage, Currently, surgical consolidation She therapy. requiring consolidation abscess cytometry. resid- of brain flow measurable fungal start no multiparameter both a and developing neutropenia, high-resolution blasts too, febrile on consolidation 03% of revealed (MRD) episodes marrow disease two bone by ual End-of-induction interrupted antimicrobials. initiated was with management chemotherapy managed appropriate phase and induction (HR) remaining High-Risk Her to upgraded was stratification risk patient’s ETV6-RUNX1, Fluorescent < %pstvt)wsreverified. was positivity) 3% . h igoi a eie to revised was diagnosis The and 5,9 TCF3-HLF ZNF384 h ieg wthmsl cusa h ieo eas.Hwvr ti lorpre npatients in reported also is it However, relapse. of time the at occurs mostly switch lineage The . in-situ uingn eutn rmarcpoa rnlcto ewe hoooe 91 ( 19p13 chromosomes between translocation reciprocal a from resulting gene fusion KMT2A ulbekaatpoe for probes break-apart dual yrdzto FS)tsigwt ulclu ulfso rbsfor probes dual-fusion dual-colour with testing (FISH) hybridization TCF3 per ob itntctgr.Baigsmlrte to similarities Bearing category. distinct a be to appears ) rnlctoswr xldduigaticlu rb Ctcl t,Cambridge). Ltd, (Cytocell probe tri-colour a using excluded were translocations re-arrangement 9 Lwt 0 icltn lss nprpea lo ma xmnto,i con- in examination, smear blood peripheral On blasts. circulating 60% with /L rnlcto nmr hn8%o el ( cells of 80% than more in translocation TCF3 TCF3-ZNF384 6–8 eragmn nbat swl sgranulocytes as well as blasts in rearrangement u cainlyas nptet with patients in also occasionally but KMT2A t1;9(1;1) eragdMA,Bmeod The B/myeloid. MPAL, rearranged [t(12;19)(p13;p13)] 2 2 and . TCF3-ZNF384 TCF3 i.1C-D Fig. CtTs n.Rcvle ntdStates) United Rockville, Inc. (CytoTest i.1E) Fig. .Tesalrlmhbat noted lymphoblasts smaller The ). pstv C-Lsaeassociated are BCP-ALLs -positive 5 n r loascae with associated also are and 12 usqety both Subsequently, . KMT2A- h rsneof presence The . ZNF384 rarne acute -rearranged 1,2 eragdacute rearranged BCR-ABL1 Fg 1F) (Fig. 7,8,10,11 ZNF384 sse nour in seen as ieversa vice . ZNF384 TCF3 4 TCF3- . (Fig. and In . 1 ) . Posted on Authorea 12 May 2020 — CC-BY 4.0 — https://doi.org/10.22541/au.158931094.41451784 — This a preprint and has not been peer reviewed. Data may be preliminary. 2 oatsAot ,Ply .Lnaesicigi ct ekma:acneuneo tmcl plasticity? cell legends: acute stem Figure of B-precursor consequence induces a leukemias: pressure acute Res in immune Marrow switching Lineage Bone CAR R. Pelayo CD19 E, al. Dorantes-Acosta plasticity. 12. leukaemic et inherent TJ, exposing Fountaine switch lineage SM, leukaemia Nguyen lymphoblastic E, rearrangement. Jacoby MLL 11. without leukemia to leukemia lymphoblastic lymphoid acute 2017;64. M acute common B, pro-B Winkler relapsed U, from of Stadt switch Zur A, Lineage Zoghbi 10. al. et rearrangement. t(12;17)(p13;q11)/TAF15-ZNF384 R, with Starza case 2013;54:1802-1805. a La in A, Following leukemia Leukemia Vitale myeloid Infant acute S, MLL-Rearranged Grammatico in Switch 9. Lineage MM. O’Brien to RL, Therapy. leukemia McMasters CD19-Directed lymphoblastic A, acute CD19-targeted Rayes B under from 8. evolution switch cytogenetic Lineage and al. t(4;11)(q21;q23) et persistent therapy. J, with leukemia Boudjarane V, monocytic leukemia Nivaggioni acute lymphoblastic E, acute Balducci KMT2A(MLL)-rearranged 7. of relapse blinatumomab. following Extramedullary switch JY. lineage Song receptor with I, leukemia. antigen Aldoss chimeric B-lymphoblastic following fusion-positive 6. switch TCF3-ZNF384 lineage Myeloid with al. patient et a Cancer D, in Bhojwani therapy PS, Gaynon T-cell MJ, acute Oberley childhood for study.5. strategy InPOG-ALL-15-01 therapeutic pilot adapted risk the of of Implementation report 2018;3:S19. EP300- al. interim et fusion, – B, recurrent acute leukaemia Arora leukaemia phenotype lymphoblastic G, lymphoblastic Narula mixed P, acute expression. of Roy Pre-B gene origin 4. distinct al. of a et cell with CH, and associated Kok basis of is SL, genetic ZNF384, Heatley subgroup The BJ, a McClure al. 3. define et I, genes Iacobucci fusion Z, ZNF384-related Gu leukaemia. TB, Alexander al. 2. immunotype. et characteristic K, a with Nakabayashi leukemia K, lymphoblastic 2017;102:118-129. acute Ohki precursor B-cell S, childhood Hirabayashi 1. References: for testing FISH leukemias. Acknowledgement: of group this in declare. occur to may statement: that interest hemato-oncologists switch of as lineage Conflict well potential as the hematopathologists of Both aware be a potential. should differentiation but multi-lineage differentiation; with lineage plasms single with conclusion, potential. pathways. leukemia differentiation In acute cell multi-lineage of stem its development unravel of initial may enrichment challenge an revealed therapeutic to have of leads MPALs profiles B/myeloid probably expression origin as gene theory, well this as of support BCP-ALLs In potential. differentiation divergent 2018;65:e27265. . n Hematol Ann Nature ZNF384- TCF3-HLF 2012;2012:406796. . 2018;562:373-379. . 2017;96:1579-1581. . h uhr r hnflt rMyrPrhr aaMdclCnr o performing for Centre Medical Tata Parihar, Mayur Dr to thankful are authors The eragdlueisaeauiu n osbyudrrcgie aeoyo neo- of category under-recognized possibly and unique a are leukemias rearranged eit lo Cancer Blood Pediatr translocation. l uhr elr htte onthv n oflc()o interest(s) of conflict(s) any have not do they that declare authors All - le ,EceihG ieg wthudrbiauoa treatment blinatumomab under switch Lineage G. Escherich I, uller ¨ Blood 2016;63:1113-1115. . 2018;131:2507. . 3 rJCancer J Br 2018;118:1000-1004. . a Commun Nat eit eao no J Oncol Hematol Pediatr eit lo Cancer Blood Pediatr ZNF384- ekLymphoma Leuk Haematologica 2 2016;7:12320. . h tmcell stem The eit Blood Pediatr rearranged . . . . Posted on Authorea 12 May 2020 — CC-BY 4.0 — https://doi.org/10.22541/au.158931094.41451784 — This a preprint and has not been peer reviewed. Data may be preliminary. CD34 CD15 2: Figure and blasts of in indicative translocation pattern unbalanced signal indicating 19p13.3 chromosome on granulocytes. gene TCF3 of and; orange) (3’end; diagnosis at blasts Fluorescent of counterstain) (Hematoxylin (A-B) 1: Figure neg neg CD33 CyCD79a muohntp fbat - blasts of Immunophenotype in-situ (G) pos CD13 Fluorescent pos opooyo lss(May-Gr blasts of Morphology yrdzto sn ulclu ra pr rb hwn eeino eoei end telomeric of deletion showing probe apart break colour dual using hybridization pos CyCD22 CD15 ZNF384 in-situ pos pos ) CyCD79a rnlcto DP counterstain). (DAPI translocation yrdzto sn ulclu ra pr rb hwn nabnormal an showing probe apart break colour dual using hybridization (E-H) (A-D) neg otcriotri rpaeteay(CD19 therapy prephase post-corticosteroid tdanss(CD19 diagnosis at CyCD22 nadGes ti;10x n myeloperoxidase-staining and 1000x) stain; Giemsa unwald ¨ 4 neg (C-D) ) tdy8ps-otcseodtherapy. post-corticosteroid day-8 at pos CD10 dimpos CD34 pos CD33 pos neg CD13 CD10 (E) (F) dim neg