*** *** *** *** T-cells T-ALL. T-cells T-ALL. T-cells T-ALL. T-cells T-ALL. T-cells T-ALL. Relative ATP content. Relative ATP content RLU RLU

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1 RLU Events Luciferin (μm) T-cells T-ALL 1 1 Time (min) T-cells T-ALL DCF-DA Reltive ATP content T-cells T-ALL RLU 1 1 T-cells T-ALL Luciferin (μm) 1 1 Time (min) c d Control e DCFH-DA (MFI) T-cells T-ALL Lctic Acid (mm) Oli FCCP N S CEM N S MT- Reltive ATP content Normlized ATP levels Control Oil -DG T-cells T-ALL CEM MT- Supplementry Figure 1. Incresed mitochondril metolism in T-ALL cells. (, ), mitochondril () nd cytosolic () ATP were mesured in norml T-cells nd primry T- ALL cells trnsfected with mitochondril luciferse (PcDNA-COX-luc) or cytosolic (PcDNAlucLL/V) luciferse. Representtive luciferse luminescence curves s function of time nd quntifiction of the luminescence s mesure of ATP content in norml T-cells (n=) nd primry T-ALL cells (n=) re shown. (c) A representtive histogrm of FACS-nlysis showing norml T-cells nd primry T-ALL cells stined with ROS-sensitive dye (DCFH-DA) nd n unstined control. An overview of the DCFH-DA fluorescence intensity (MFI) in norml T-cells (n=) nd primry T-ALL cells (n=) re shown. (d) Lctic cid levels in CEM nd MT- cells fter tretment with the oxidtive phosphoryltion inhiitor oligomycin (Oli, μm) or FCCP ( μm ) for h. (e) ATP levels were mesured in CEM nd MT- cells fter tretment with oligomycin (Oli, μm) or the glycolysis inhiitor -DG, ( μm) for h. The dt represent men ± S.D. vlue from n experiment performed in triplicte. p <.1, p <.1,, not significnt, Student s t test.

2 1KD 1KD KD KD c T-ALL 1 T-ALL T-ALL d Jurkt CEM Molt- MT- 1KD 1KD KD KD e f g OCR(µs/h) h Normlized ATP levels T-ALL 1 T-ALL T-ALL * * CEM MT- N S sh N S CEM MT- CEM MT Lctic Acid (mm) i OCR(µs/h) Normlized ATP levels sh CEM sh sh+ MT- Jurkt CEM Molt- MT- Normlized ATP levels Supplementry Figure. Western lot nlysis of expression nd the role of in mitochondril metolism of T-ALL cells. (, ) Western lot nlysis of knockdown efficiency in primry T-ALL cells () nd T-ALL cell lines (). (c, d) Western lot nlysis of overexpression in primry T-ALL cells (c) nd T-ALL cell lines (d). (e) Bseline OCR nd lctic cid levels in CEM nd MT- cells with knockdown. (f) ATP levels in CEM nd MT- cells with knockdown. (g) Bseline OCR nd lctic cid levels in CEM nd MT- cells with overexpression. (h) ATP levels in CEM nd MT- cells with overexpression. (i) Bseline OCR (left) nd ATP levels (right) in or sh lentivirus-infected Jurkt T-cells nd shinfected cells re-trnsfected with. The dt represent men ± S.D. from n experiment performed in triplicte. *p <., p <.1, p <.1,, not significnt, Student s t test. OCR(µs/h) * N S N S CEM MT- CEM MT Lctic Acid (mm)

3 T-cells T-ALL 1 1 PTEN KD Notch-1 KD 1KD KD T-cells T-ALL PTEN KD Notch-1 KD 1KD KD PTEN KD KD Supplementry Figure. Western lot nlysis of PTEN nd Notch-1 sttus in norml T-cells nd primry T-ALL cells (), nd of PTEN sttus in the T-ALL cell lines used ().

4 PLC β Hoechst Merge sh T P C N T P C N KD 1KD P-cd 1KD HA 1KD c P-cd Reltive levels e f Control P C P C P C P C Control DSP sh sh + p- DSP Control Unstimulted 1KD 1KD KD d Merge I pm I nu Ipm Responding cells (%) 1 p- stimultion I nu Merge Responding cells (%) Intensity rtio I pm / I nu sh sh+. Intensity rtio I pm / I nu.... sh sh KD

5 Supplementry Figure. knockdown prevents trnsloction to the plsm memrne nd ctivtion. () Immunofluorescence stining with nti- showing nucler locliztion of the protein. Hoechst stining indictes the nucleus. Scle rs, 1 μm. () Control nd knockdown Jurkt T-cells were treted for min in the presence or sence of 1 μg/ml nti-cd. The totl (T), plsm memrne (P), cytosolic (C) nd nucler (N) frctions were nlyzed y western lot. Pn-cdherin, histone HA nd ctin were used s loding controls for the plsm memrne, nucler nd cytosolic frctions, respectively. (c) Jurkt T-cells were treted for min in the presence or sence of 1 μg/ml nti-cd, nd then cells were cross-linked y 1mM DSP for min efore lysis. The plsm memrne (P) nd cytosolic (C) frctions were nlyzed y western lot. (d) trnsloction in control nd knockdown Jurkt T-cells upon 1 μg/ml nti- CD stimultion for min (upper, left). The percentge of cells responding to nti- CD is represented s histogrm (upper, right) (1 cells from three experiments with 1 rndom fields/experiment). A line intensity profile cross the cell ws otined in given imge (upper, left). Representtive intensity profiles re shown (lower, left). The reltive fluorescence intensity rtio of plsm-memrne-djcent re (I pm ) versus nucler re (I nu ) re shown (lower, right; cells from three experiments with 1 rndom fields/experiment). (e) trnsloction in or sh lentivirus-infected Jurkt T-cells nd sh -infected cells re-trnsfected with. Cells were stimulted for min in the presence or sence of 1 μg/ml nti-cd. The percentge of cells responding to nti-cd (1 cells from three experiments with 1 rndom fields/experiment) nd the reltive fluorescence intensity rtio of plsm-memrne-djcent re (I pm ) versus nucler re (I nu ) re shown ( cells from three experiments with 1 rndom fields/experiment). Scle rs, 1 μm. (f) Confocl microscopy nlysis of (green) nd p- (red) locliztion in Jurkt T-cells. Cells were stimulted for min in the presence or sence of 1 μg/ml nti-cd. Scle rs, 1 μm. The dt represent men ± S.D. from n experiment performed in triplicte. p <.1, p <.1, Student s t test.

6 c PLC β PLC 1 PLC β PLC 1 PLC β PLC 1 1KD 1KD KD 1KD 1KD KD 1KD 1KD KD IP IP IP shplc 1 shplc F/F F/F shplc 1 shplc shplc 1 shplc F/F 9 7 F/F.. 1 F/F F/F (1μg/ml) shplc 1 shplc 1 1 Time (min) (1μg/ml) shplc 1 7 shplc Time (min) 7 1 (1μg/ml) 1 1 Time (min) shplc 1 shplc d PLC β PLC 1 1KD 1KD KD IP 1 1 PLC 1 PLC * F/F 7 1 * F/F 7 1 (1μg/ml) 1 1 Time (min) PLC 1 PLC

7 Supplementry Figure. is essentil for C + relese in T-ALL cells. Mesurement of nti-cd induced IP production nd [C + ] i trnsients upon PLC or PLC 1 knockdown in () norml T-cells, () primry T-ALL cells, nd (c) Jurkt T-cells. (d) Mesurement of nti-cd induced IP production nd [C + ] i trnsients upon PLC or PLC 1 overexpression in Jurkt T-cells. IP concentrtion ws determined y stimultion of cells with 1 μg/ml nti-cd for min. [C + ] i were recorded s F/ rtio using Fur-AM in cells with 1 μg/ml of nti-cd stimultion. Averge [C + ] i responses nd quntifiction of [C + ] i pek mplitudes of norml T-cells or primry T- ALL cells re shown. For the Jurkt T-cells the dt represent men ± S.D. vlue from n experiment performed in triplicte, nd for primry T-cells nd T-ALL cells men ± S.D. vlue of n= primry T-ALL specimens. *p<., p <.1,, not significnt, Student s t test.

8 sh c d IP IP sh+ PIP Control. 1 1 PIP IP IP shplc Control PIP sh IP IP PLC sh Control PIP Supplementry Figure. modultes IP production. () IP production in or sh trnsduced Jurkt T-cells nd sh trnsduced cells re-trnsfected with. () IP production in Jurkt T-cells overexpressing lone or in comintion with sh. (c) IP production in or sh trnsduced Jurkt T-cells with or without overexpression. (d) IP production in wild-type Jurkt T- cells incuted with incresing concentrtions of exogenous PIP (left), nd knockdown (middle) or overexpressing (right) cells fter tretment with 1 nm PIP. Cells were incuted with PIP for 1 h efore min stimultion with 1 μg/ml nti-cd. The dt represent men ± S.D. vlue from n experiment performed in triplicte. p <.1, p <.1, Student s t test.

9 F/ c F/F e F/F g Totl c + (mm) EGTA (1μg/ml) 1 1 TG (nm) sh (1μg/ml) 1 1 Time(min) Time(min) sh sh 1 1 Time(min) sh Control C + F/ F/F F/F Totl c + (mm) sh C + relese C+ influx sh sh Control F/ d f F/F F/F EGTA.. (1μg/ml) (1μg/ml) Time(min) C TG (nm) Time(min) 1 1 Time(min) F/ F/F F/F * C + relese C+ influx

10 Supplementry Figure 7. regultes C + relese from ER in Jurkt T- cells. (, ) Jurkt T-cells sujected to knockdown () or overexpression () were stimulted with 1 μg/ml nti-cd in ECB (contining1 mm EGTA) without C +. Chnges in [C + ] i were recorded s the F/ rtio using Fur-AM. After stimultion, ECB contining mm CCl insted of EGTA were used to nlyze C + influx. Averge [C + ] i responses nd quntifiction of [C + ] i pek mplitudes re shown. (c, d) Jurkt T-cells sujected to knockdown (c) or overexpression (d) were stimulted with 1 μg/ml nti-cd in ECB. Chnges in [C + ] i were recorded s the F/F rtio using FluoN-AM. Averge [C + ] E responses nd quntifiction of [C + ] E pek mplitudes re shown. (e, f) Jurkt T-cells sujected to knockdown (e) or overexpression (f) were stimulted 1 nm TG in ECB. Chnges in [C + ] i were recorded s the F/ rtio using Fur-AM. (g) Totl mount of C + in Jurkt T-cells sujected to knockdown nd overexpression in the presence or sence of 1 μg/ml nti-cd stimultion. The dt represent men ± S.D. vlue from n experiment performed in triplicte. *p <., p <.1,, not significnt, Student s t test.

11 N sh E M E N M Incidence of the tight ssocitions (%) 1 1 sh sh ER DsRed-ER /Mito / Merge / GFP-Mito ER DsRed-ER /Mito / Merge / GFP-Mito Person's correltion CFP-Mito / DsRed-ER..... sh Supplementry Figure. knockdown filed to chnge the quntity of ER-mitochondril contcts in Jurkt T-cells. () TEM imging of ERmitochondril contct sites (red rrowheds depicting the close contcts) in control nd knockdown Jurkt T-cells, nd mesurements of the ER mitochondri interfce (N, nucleus; M, mitochondrion; E, endoplsmic reticulum), Scle rs, nm. () Confocl microscopy nlysis of the colocliztion of ER (red) nd mitochondri (green). Scle rs, 1 μm. Person s correltion of the ER nd mitochondril signls is represented ( cells were nlyzed per condition). The dt represent men ± S.D. vlue from n experiment performed in triplicte., not significnt, Student s t test.

12 sh BODIPY-Chol DsRed-Mito Merge Person's correltion BODIPY-Chol / DsRed-Mito..... sh sh BODIPY-Chol DsRed-ER Merge Person's correltion BODIPY-Chol / DsRed-ER sh Supplementry Figure 9. knockdown does not chnge the trnsport of BODIPY-cholesterol from the PM to ER or mitochondri. Control nd knockdown Jurkt T-cells were trnsfected with mitochondril (DsRed-Mito) () or ER (DsRed-ER) mrker () for h. The cells were then leled for 1 min with BODIPY-chol, chsed for min, nd confocl imges were tken fter the chse. Scle rs, 1 μm. Brs indicte Person s correltion of BODIPY-chol nd ech orgnelle DsRed mrker ( cells were nlyzed per condition). The dt represent men ± S.D. vlue from n experiment performed in triplicte., not significnt, Student s t test.

13 T-cells T-ALL 1 1 ORPM p p ORPS p c Xpress 1KD 7KD KD IP 1 1 KD d F/ 7 (1μg/ml) ORPM ORPS ( PH) ( FFAT) (PH) F/ Time(min) Supplementry Figure 1. The effects of ORPM, ORPS nd truncted or mutted constructs on C + signling. () RT-PCR nlysis of, ORPM nd ORPS expression in norml T-cells, primry T-ALL cells nd T-ALL cell lines. () Western lot verifying overexpression of the constructs used in Jurkt T-cells, s detected y Xpress epitope tg ntiody. (c, d) IP production (c) nd C + response (d) upon nti-cd stimultion in Jurkt T-cells overexpressing the indicted constructs. The dt represent men ± S.D. vlue from n experiment performed in triplicte. p <.1,, not significnt, Student s t test.

14 sh JC-1 (Red/Green Rtio) 1.. sh. sh NAD(P)H fluoresence per cell (ritry unit) 1 9 sh * Supplementry Figure 11. knockdown reduces the mitochondril memrne potentil nd NAD(P)H utofluorescence in Jurkt T-cells. () Mitochondril memrne potentil ws visulized with epifluorescence microscopy nd expressed s rtio of JC-1 ggregtes (red) nd monomer (green) (Red/Green). () NAD(P)H utofluorescence ws cptured with DAPI cue y epifluorescence microscopy nd used to clculte FCCP-sensitive mitochondril NAD(P)H level [ΔNAD(P)H] per cell. Scle rs, 1 μm. The dt represent men ± S.D. (n=). *p<., p <.1, Student s t test.

15 1KD KD IP 1 OCR (us/h) Normlized ATP levels Supplementry Figure 1. overexpression filed to ffect oxidtive phosphoryltion in norml T-cells. () Western lot verifying the overexpression of in trnsfected T-cells. () IP production (left), OCR (middle) nd ATP levels (right) in control nd overexpressing T-cells. The dt represent men ± S.D. vlue from n experiment performed in triplicte., not significnt, Student s t test.

16 Fig. 1f Fig. Fig. c 1KD CDε 1KD CDε 1KD KD Gα q/11 KD 1KD Gα q/11 1KD KD 1KD 1KD Gα q/11 KD 1KD KD CDε 1KD CDε 1KD Fig. 1g 1KD 1KD 1KD 1KD Gα q/11 KD KD Fig. d Fig. e CDε 1KD CDε 1KD 1KD 1KD Gα q/11 KD Gα q/11 KD Fig. CDε 1KD 1KD 1KD CDε Gα q/11 1KD 1KD 1KD KD p- Gα q/11 1KD 1KD KD KD Fig. c Fig. d 1KD 1KD p- 1KD p- 1KD 1KD KD 1KD KD p- 1KD 1KD 1KD KD p- 1KD 1KD 1KD KD Supplementry Figure 1. Representtive originl imges of immunolotting results for Figure 1-. The cropped res used in the figures re mrked y oxes.

17 Fig. Fig. Supplementry Figure 1. Continued p-pdh KD p-pdh KD PDH KD PDH KD KD KD Fig. c Fig. d Fig. e 1KD p-pdh KD p-pdh KD p-pdh KD PDH KD PDH KD KD KD PDH KD KD Fig. f Fig. g Fig. h p-pdh KD p-pdh KD p-pdh KD PDH KD PDH KD PDH KD KD KD KD Fig. e Fig. g 1KD p-ampk KD KD AMPK KD Fig. f LC I LC II 1KD p-ampk KD KD AMPK KD Fig. i LC I LC II 1KD p-pdh KD p-mtor KD PDH KD mtor Fig. h KD KD p-ampk AMPK KD KD LC I LC II 1KD LC I LC II 1KD KD KD

18 Supplementry Tle 1. Summry of the clinicl T-ALL cell smples nd their nlyses Anlyses performed Smples Age Sex Western Cofocl ATP OCR ECAR q-pcr IP C + lot imge Cell Engrftment deth ROS PDH/AMPK ctivity, utophgy T-ALL 1 M Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes T-ALL 1 F Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes T-ALL M Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes T-ALL M Yes Yes Yes T-ALL F Yes Yes Yes Yes T-ALL F Yes Yes Yes Yes Yes Yes T-ALL 7 1 M Yes Yes T-ALL 7 M Yes Yes Yes Yes T-ALL 9 F Yes Yes T-ALL 1 19 M Yes Yes T-ALL 11 M Yes Yes T-ALL 1 F Yes Yes T-ALL 1 M Yes Yes T-ALL 1 F Yes Yes Yes Yes Yes Yes T-ALL 1 9 F Yes Yes T-ALL 1 1 F Yes Yes Yes T-ALL 17 M Yes Yes Yes Yes Yes Yes T-ALL 1 M Yes Yes

19 Supplementry Tle. Puttive -intercting proteins Symol Entrez Gene Nme HCLS1 Hemtopoietic linege cell-specific protein DARS Asprtyl-tRNA synthetse A1S9T Uiquitin-like modifier-ctivting enzyme 1 CDE T-cell surfce glycoprotein CD epsilon chin RPL7 S riosoml protein L7 JUP Puttive unchrcterized protein EP1 CGI- PAI1 RNA-inding protein 1 phosphtidylinositol-,-isphosphte phosphodiesterse et- FUBP Fr upstrem element-inding protein EVL En/vsodiltor-stimulted phosphoprotein-like RABEP R GTPse-inding effector protein Gαq/11 Gunine nucleotide inding protein, lph q/11 NUDC Nucler distriution protein C homolog DRBF Doule-strnded RNA-inding protein 7

20 Supplementry Tle. The trgeted shrna sequences used Construct sense - Anti-sense - GCATTGGTCGTCTCT ATTA TAATAGAGACGACCAATGC sh TCAGAGTCAAGCTCAGGTGTA TACACCTGAGCTTGACTCTGA sh AGATGAGGGACAAGCATAAGAAGGA TCCTTCTTATGCTTGTCCCTCATCT shplcγ1 AAACAACCGGCTCTT CGT ACGAAGAGCCGGTTGTTT sigq/11 GGAGUACAAUCGGUCUAAUU UUAGACCAGAUUGUACUCCUU

21 Supplementry Tle. Oligonucleotide primers used for cdna constructs Construct Forwrd primer - Reverse primer - -pcdna HisMxC ATTtctgATGGGGAAAGCGGCGGT* ATTtctgGTGGCGCTCAGAAGATGTTG GGGCACATATGCCA ORPM-pcDNA HisMxC ATTgtctATGTCGTCACTGGCAGCGAAG ATTgtcgcGAAGATGTTGGGGCACATATG ORPS-pcDNA HisMxC ATTgtctATGGAAGACTCCACATCCTTCA ATTgtcgcGAAGATGTTGGGGCACATATG ( PH)-pcDNAHisMxC Forwrd 1: ATTgtctATGGGGAAAGCGGCGGCT Forwrd 1: GCTGTCCAGAGGCAGTAAGGCGTCCCCAGA GTCATCTGAA Reverse 91: ATTgtcgcGAAGATGTTGGGGCACATATGCCA Reverse 1: TTCAGATGACTCTGGGGACGCCTTACTGCCTCT GGACAGC ( FFAT)-pcDNAHisMxC Forwrd 1: ATTgtctATGGGGAAAGCGGCGGCT Forwrd : TGATGAAGGATGTGGAGTCTTCCATGGTATC TTCATCTTCCTCACTGTCC Reverse 91: ATTgtcgcGAAGATGTTGGGGCACATATGCCA Reverse : GGACAGTGAGGAAGATGAAGATACATGGAAGA CTCCACATCCTTCATCA (PH)-pcDNAHisMxC ATTgtctGTGAGGGCTGGCTTCTCAAGT ATTgtcgcCTTGGCCAGCTCCAGGGCGGTGAT -pcdnahismxc ATTgttcATGGCGGGCGCCCAGCCCGGC ATTctcggTCAGAGCTGCGTGTTCTCCT PLCγ1-pcDNAHisMxC ATTgttcATGGCGGGCGCCGCGTCCCCTT ATTtctgCTAGAGGCGGTTGTCTCCATTGACC *Restriction sites re indicted in lower cse letters.

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