Negative feedback-defective PRPS1 mutants drive … · Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL ... S1 03 24h Ve cto r W

1

SUPPLEMENTARY INFORMATION

Negative feedback-defective PRPS1 mutants drive thiopurine

resistance in relapsed childhood ALL

Benshang Li1,5, §, Hui Li1,5, §, Yun Bai2,§, Renate Kirschner-Schwabe3,10, Jun J Yang4, Yao Chen1,5,

Gang Lu2, Gannie Tzoneva6, Xiaotu Ma4, Tongmin Wu1,5,7, Wenjing Li8, Haisong Lu9, Lixia

Ding1,5, Huanhuan Liang1, Xiaohang Huang1, Minjun Yang2, Lei Jin2, Hui Kang2, Shuting Chen2,

Alicia Du9, Shuhong Shen1,5, Jianping Ding8, Hongzhuan Chen7,11, Jing Chen1, Arend von

Stackelberg3, Longjun Gu1*, Jinghui Zhang4, Adolfo Ferrando6,*, Jingyan Tang1,*, Shengyue

Wang2,11* & Bin-Bing S. Zhou1,5,7,11*

Nature Medicine: doi:10.1038/nm.3840

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Supplementary Figures

Supplementary Figure 1 CIRCOS plot of genetic alterations identified through whole-exome

sequencing of 15 matched triad diagnosis-remission-relapse childhood ALL samples. The

inner pink, green, and pale blue circles represent the diagnosis-specific, diagnosis and relapse

shared, and relapse-specific mutations, respectively. Interchromosomal translocations are

indicated by different curves across the center of CIRCOS plot.


3

Supplementary Figure 2 From top to bottom, clinical characteristics, substitution frequency,

single nucleotide variants (SNV) and copy number alterations (CNA) in 15 individuals at

diagnosis (D) and relapse (R).


4

Supplementary Figure 3 Mutations at diagnosis (D) and relapse (R). Mutant Allele

Fraction (MAF) identified by intensity of red (SNV) and blue (indel). CNAs (including deletion

and amplification) are shown in grey. Cases with oncogenic fusions involving BCR-ABL,

TEL-AML1, MLL-AF4 and MLL-rearrangement are marked at the top along with

immunophenotype.


5

Supplementary Figure 4 The comparable expression levels of wild-type and mutant PRPS1 in

lentivirus infected Reh cells. The same cell numbers were used for making cell lysates, and actin

was shown as a loading control.

Supplementary Figure 5 Viability of Reh cells expressing wild-type PRPS1, relapse-specific

PRPS1 mutated alleles or vector only (GV303), treated with increasing concentrations of 6-MP

or 6-TG. Data are shown as the means ± s.d.

His-PRPS1

Actin

Vect

WT

S10

S10

N14

K17

D18

A19

L19

T30

D18

A19

Vect

WT

N11

G17

V53

I72V

C77

D13

Y31

S10


6

Supplementary Figure 6 Viability of Reh cells expressing wild-type NT5C2, relapse-specific

R238W mutant or vector treated with increasing concentration of 6-MP or 6-TG. Data are

shown as the means ± s.d.

Supplementary Figure 7 Viability of cells expressing wild-type PRPS1 and various PRPS1

mutants including activating and reduced-function mutants. Data are shown as the means ±

s.d.


7

Supplementary Figure 8 All relapse-specific mutation residues of PRPS1 mapped on the

crystal structure of human PRPS1 dimer showing one subunit in beige and the other in tan.

Docked ATP and GDP are shown as yellow and red stick, respectively. Cα atoms of mutant

residues are shown as spheres. Drug-resistant mutations reported in this work are colored in

green, while mutations with unknown function colored in magenta.


8

Supplementary Figure 9 Viability of Reh cells expressing control or PRPS1 shRNAs were

treated with increasing concentration of 6-MP and 6-TG. Data are shown as the means ± s.d.

Supplementary Figure 10 Viability of Jurkat cells expressing wild-type PRPS1,

relapse-specific PRPS1 mutant alleles or vector treated with increasing concentrations of 6-MP.

Values were shown as IC50. Data are shown as the means ± s.d.


9

Supplementary Figure 11 Viability of Reh cells expressing wild-type PRPS1 or mutants

treated with increasing concentrations of methotrexate (MTX), cytosine arabinoside (AraC),

daunorubicin (DNR) or L-asparaginase (L-ASP). Data are shown as the means ± s.d.

Supplementary Figure 12 DNA damage response and apoptosis biomarkers in western blot

analysis of Reh cells with the indicated PRPS1 mutations. Reh cells were treated with 1g/ml

6-MP for indicated time and lysed for immunoblot with different antibodies.

Chk2(T68)

Actin

Chk2

H2AX (S139) H2AX

Reh Ve

ctor

WT

A190T

8h Vector

WT

A190T

S103T

24hVector

WT

S103T

48hA190T

S103T


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Supplementary Figure 13 Intracellular TGMP measured by LC-MS in Reh cells expressing

various PRPS1 mutants treated with 10 M 6-MP for 4 hr. Values are relative concentrations

estimated based on standard curves of pure compounds without correcting for the cell matrix’s

effect, data are shown as the means ± s.d.

Supplementary Figure 14 Identification of 6-MP metabolite derivatives in Reh cells

expressing different PRPS1 variants by LC-MS. Upon de-phosphorylation treatment with

phosphatase, r-MP and r-MMP were surrogates for TIMP, r-TG was surrogate for TGMP,

respectively. Data are shown as the means ± s.d.


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Supplementary Figure 15 Measurement of PRPS1 cellular activity by [13C5]-PRPP in Reh

cells. Values were direct reading from LC-MS. Data are shown as the means ± s.d.

Supplementary Figure 16 IMP synthesis (flux) through the de novo purine synthesis pathway

was measured by [13C2, 15N] incorporation into cells. IMP and HX were measured directly by

LC-MS. The HX cellular concentration was estimated by a standard curve using isotope-labeled

HX with cell matrix effect corrected. Data are shown as the means ± s.d.


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Supplementary Figure 17 Identification of IMP in Reh cells by LC-MS. Total IMP

concentration=the concentration of unlabeled plus labeled IMP. Data are shown as the means

± s.d.

Supplementary Figure 18 Western blot analysis of PRPS1 protein purified from E.coli.


13

Supplementary Figure 19 Viability of Reh cells at increasing concentrations of 6-MP in the

presence of IMP. Data are shown as the means ± s.d.

Supplementary Figure 20 Cell viability for Reh cells treated with increasing concentrations

of 6-TG in the presence of hypoxanthine (HX) and IMP, respectively. Data are shown as the

means ± s.d.


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Supplementary Figure 21 DNA damage response and apoptosis biomarkers in western blot

analysis of Reh cells with indicated treatment. Reh cells were mock treated, treated with 6-MP

or 6-TG in the presence of IMP or hypoxanthine (HX), and lysed for immunoblot analysis of

H2AX (S139), pCHK2 (T68), cleaved PARP and their corresponding native forms.

Supplementary Figure 22 Reh cells were treated with 10 M 6-MP in the presence of

different nucleotides, then intracellular TGMP was measured by LC-MS. Data are shown as

the means ± s.d.


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Supplementary Figure 23 The HPRT1-catalyzed 6-MP conversion into TIMP and

[13C5,15N4]-HX into [13C5,

15N4]-IMP were measured simultaneously in Reh cells by following

different peaks using LC-MS and were shown as normalized activity. Data are shown as the

means ± s.d.

Supplementary Figure 24 IMP inhibition of HPRT1 enzymatic activity showing the titration

curve with increasing IMP concentration.


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Supplementary Figure 25 De novo pathway blockage by gene knock down is sufficient to

reverse the drug resistance and HX increase caused by PRPS1 mutants. Cell viability of Reh

cells expressing wild-type or drug resistant A190T and S103T PRPS1 treated with increasing

amount of 6-MP with or without ATIC or GART knock-down by CRISPR-CAS9. The

concentrations of HX from the same set of samples were measured by LC-MS. Data are shown

as the means ± s.d.

Supplementary Figure 26 Viability of Reh cells with or without 5 ng/ml GART inhibitor

lometrexol. HX and TGMP were measured in the same sample set by LC-MS. Data are

shown as the means ± s.d.


17

Supplementary Tables

Supplementary Table 1. Characteristics of 16 cases of children with relapsed ALL in Chinese cohort

Patient ID

Age at diagnosis

(year) Sex

WBC (×109)

Cytogenetics Immunoph

enotype

BM Blast at diagnosis

(%)&

BM Blast at relapse (%)&

Time interval (Month)¶

ALL-004 7.39 Male 1.9 Hyperdiploid

(54~55) B 86.4% 58.4% 40.6

ALL-023 7.85 Male 100.9 Normal B 86.4% 62.0% 11.4 ALL-024 4.70 Male 20.9 Normal B 90.0% 75.2% 9.1 ALL-039 3.58 Male 57.1 Normal B 93.6% 67.2% 10.9 ALL-057 9.62 Male 138.7 Normal T 91.2% 90.0% 10.6 ALL-058 4.59 Female 158.0 Normal B 94.0% 93.6% 17.2 ALL-059 0.41 Female 386.8 t(4;11) B 99.2% 82.8% 6.5 ALL-060 7.15 Male 183.8 Normal T 95.2% 97.2% 18.3 ALL-061 5.25 Female 508.8 t(9;22) B 96.4% 83.0% 7.4 ALL-062 8.77 Female 269.2 Normal T 94.4% 88.8% 11.0 ALL-063 4.57 Male 15.5 t(12;21) B 90.4% 96.0% 46.3

ALL-064 13.07 Male 105.0 der(21); t(9,21)

T 91.2% 72.8% 10.8

ALL-065 9.18 Male 55.6 del(9)(q22) B 87.4% 44.6% 13.0

ALL-066 3.00 Male 242.6 der(11); t(11;14);

del(14)(q12) T 87.2% 65.2% 10.9

ALL-067 6.00 Male 16.6 t(9;22) B 90.0% 84.0% 4.3 ALL-076 6.76 Male 2.9 t(9;22) B 86.4% 97.2% 32.9

& BM blast ratio at diagnosis and relapse were identified by bone marrow morphology observe, samples were separated by Ficoll-Hypaque density gradient centrifugation before cryopreserved. ¶ Months elapsed from diagnosis to relapse.


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PD

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TF

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133

117

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3 12

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p.R

385H

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62

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2292

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29

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34

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62

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C11

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0.91

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62

CSP

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5:75

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59

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99

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62

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1840

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L95

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0.02

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66

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2:10

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146

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24

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62

PT

PL

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1 ch

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01

1

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L-0

62

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MO

3 ch

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6723

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62

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ch

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3417

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p.R

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62

LB

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0:36

9976

97

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32

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0

32

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p.P

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1

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62

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66

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71

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63

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1:11

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63

NA

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2:78

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63

SLIT

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63

XIR

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2648

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29

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11

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0

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63

FA

T4

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63

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63

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CH

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2963

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110

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R30

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63

EIF

4A1

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7:74

8119

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p.R

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0.76

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63

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F25

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15

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63

NL

RC

4 ch

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2475

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17

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p.T

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22

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63

OST

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9595

3834

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14

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63

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52

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63

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63

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DH

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51

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A

11

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no

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63

MB

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T1

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p.M

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72

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63

PO

T1

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63

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64

NF

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ch

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07

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64

CY

P2C

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no

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64

ASP

HD

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64

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11

8

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12

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p.T

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64

TM

PR

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1971

5822

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80

27

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92

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64

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27

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4258

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1 ch

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64

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14

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p.A

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16

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64

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P

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1:76

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57

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15

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158M

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64

PSP

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3:20

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76

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30

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64

AB

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11

chr2

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30

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87

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134

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64

PO

LQ

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65

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58

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CX

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545

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26

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MT

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27

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17

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7:73

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7

23

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4

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0.57

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65

NC

BP

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9666

4445

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9311

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26

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66

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ch

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20

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66

PIK

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47

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57

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102

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66

LR

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41

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66

H2B

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2677

70

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p.E

155K

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L-0

66

MU

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ch

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1247

968

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10

6

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41

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66

TC

P11

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2:10

6712

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64

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106

17

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66

LT

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6

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66

SLC

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6:55

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17

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8

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12

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p.G

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N

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77

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66

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EP

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2:41

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66

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66

CSM

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XD

4 ch

r2:1

7701

6609

D

RSV

G

A

8

5 8

0 13

6

nons

ynon

ymou

s p.

G83

D

0.39

0

AL

L-0

67

AQ

P12

B

chr2

:241

6221

03

DR

SV

A

C

28

7 8

0 24

5

nons

ynon

ymou

s p.

F51

C

1 0

AL

L-0

67

WD

R36

ch

r5:1

1045

4715

D

RSV

A

C

41

13

38

1

56

26

nons

ynon

ymou

s p.

I657

L 0.

11

0.02

AL

L-0

67

BR

D9

chr5

:878

525

DR

SV

T A

18

2

14

0 29

8

nons

ynon

ymou

s p.

M40

6L

0.33

0

AL

L-0

67

MX

RA

5 ch

rX:3

2289

55

DR

SV

G

A

15

13

9 0

14

13

nons

ynon

ymou

s p.

T24

30M

0.

14

0.46

AL

L-0

67

KIA

A18

04

chr1

:233

4978

36

DSV

C

A

23

4

11

0 24

0

nons

ynon

ymou

s p.

A45

0D

0 0.

99

AL

L-0

67

GU

CY

1A2

chr1

1:10

6810

308

RSV

C

A

51

0

23

0 45

7

nons

ynon

ymou

s D

362Y

0.

03

0.91

AL

L-0

67

AB

L1

chr9

:133

7482

83

RSV

C

T

27

0 15

0

35

12

nons

ynon

ymou

s p.

T31

5I

0 1

AL

L-0

76

PA

MR

1 ch

r11:

3551

5694

D

RSV

G

A

44

15

45

0

49

14

nons

ynon

ymou

s p.

P67

L 0

1

AL

L-0

76

DC

HS1

ch

r11:

6647

863

DR

SV

G

T 10

1 40

79

1

104

48

nons

ynon

ymou

s p.

A20

95E

0.

22

0.08

AL

L-0

76

TN

PO

1 ch

r5:7

2147

135

DR

SV

T G

44

13

35

0

49

22

stop

gain

p.

L57

X

- -


29

AL

L-0

76

RH

PN

2 ch

r19:

3349

0566

D

SV

T C

20

4

13

0 15

0

nons

ynon

ymou

s p.

Q38

4R

0.01

0.

86

AL

L-0

76

SPE

F2

chr5

:356

4462

8 D

SV

G

C

40

7 24

0

38

0 sp

lici

ng

- -

-

AL

L-0

76

MA

RK

1 ch

r1:2

2082

6558

R

SV

C

T 43

1

53

0 51

25

st

opga

in

p.Q

618X

-

-

AL

L-0

76

C10

orf9

1 ch

r10:

1342

6124

2 R

SV

C

A

60

0 45

0

44

19

nons

ynon

ymou

s p.

P39

T -

0.01

AL

L-0

76

KB

TB

D4

chr1

1:47

5991

37

RSV

C

A

11

4 0

67

0 93

38

no

nsyn

onym

ous

p.A

139S

0.

4 0.

01

AL

L-0

76

GC

N1L

1 ch

r12:

1206

1554

3 R

SV

C

G

95

1 75

0

85

36

nons

ynon

ymou

s p.

D22

5H

0.01

0.

4

AL

L-0

76

CH

D8

chr1

4:21

8765

24

RSV

G

C

16

3 0

114

0 14

8 67

no

nsyn

onym

ous

p.L

614V

0.

42

0.99

AL

L-0

76

LO

C81

691

chr1

6:20

8331

69

RSV

G

T

71

0 58

0

55

27

nons

ynon

ymou

s p.

L18

7F

0.01

1

AL

L-0

76

SRSF

1 ch

r17:

5608

4319

R

SV

C

G

24

0 28

0

28

12

nons

ynon

ymou

s p.

E60

D

0.05

0.

17

AL

L-0

76

KIA

A17

55

chr2

0:36

8744

32

RSV

G

A

24

0

21

0 26

12

no

nsyn

onym

ous

p.R

34C

0

0.89

AL

L-0

76

PT

PR

G

chr3

:621

4276

7 R

SV

G

A

57

0 37

0

53

20

nons

ynon

ymou

s p.

V23

7I

0.64

0.

03

AL

L-0

76

FA

M14

9A

chr4

:187

0881

86

RSV

G

T

55

0 52

0

59

30

nons

ynon

ymou

s p.

R41

0L

0.21

0.

01

AL

L-0

76

SCD

5 ch

r4:8

3582

060

RSV

C

T

135

0 10

8 0

111

47

nons

ynon

ymou

s p.

R24

7H

- 0

AL

L-0

76

KC

NK

5 ch

r6:3

9196

746

RSV

C

G

33

0

41

0 27

8

nons

ynon

ymou

s p.

E48

Q

0.52

0

AL

L-0

76

KIF

C2

chr8

:145

6948

94

RSV

G

C

22

0

15

0 25

13

no

nsyn

onym

ous

p.R

415P

0

1

AL

L-0

76

PR

PS1

ch

rX:1

0688

5621

R

SV

A

G

31

0 24

0

43

38

nons

ynon

ymou

s p.

N14

4S

0 0.

2

Ind

els

AL

L-0

04

TT

N

chr2

:179

6112

08

RSV

G

AG

A

G

37

0 66

0

35

11

Cod

en d

elet

ion

p.S5

306-

-

-

AL

L-0

23

SMC

3 ch

r10:

1123

6265

2 D

RSV

G

G

TA

GC

68

33

80

0

60

24

Fra

me

shif

t -

- -

AL

L-0

23

MA

ML

2 ch

r11:

9582

5371

D

SV

CT

GT

C

19

8

17

0 31

0

Cod

en d

elet

ion

p.Q

Q60

7Q

- -

AL

L-0

23

PE

LP

1 ch

r17:

4575

583

DSV

C

TC

T C

13

6

9 0

10

0 C

oden

del

etio

n p.

EE

900E

-

-

AL

L-0

24

MY

T1

chr2

0:62

8393

98

RSV

G

GA

A

G

36

0 24

0

27

9 C

oden

del

etio

n p.

E28

4-

- -

AL

L-0

24

TP

RK

B

chr2

:739

5777

3 R

SV

GA

TTT

G

52

0

42

0 37

17

F

ram

e sh

ift

- -

-

AL

L-0

24

NIP

BL

ch

r5:3

7049

231

RSV

A

G

A

101

0 68

0

75

24

Fra

me

shif

t -

- -

AL

L-0

57

DN

AH

5 ch

r5:1

3766

238

DR

SV

A

AG

19

0 92

46

0

152

52

Fra

me

shif

t -

- -

AL

L-0

57

PK

N3

chr9

:131

4806

15

DSV

-

G

228

34

47

0 19

6 0

Fra

me

shif

t

-

-

AL

L-0

57

NC

OA

3 ch

r20:

4627

9833

R

SV

GC

AA

G

38

0

63

0 26

14

C

oden

del

etio

n p.

Q12

45-

- -

AL

L-0

57

ZN

F64

9 ch

r19:

5239

4471

R

SV

AA

C

- 20

6 0

79

0 21

7 21

C

oden

del

etio

n p.

V30

6del

-

-

AL

L-0

57

SEC

24B

ch

r4:1

1042

7585

R

SV

G

GA

74

0

157

0 15

2 67

F

ram

e sh

ift

- -

-

AL

L-0

57

VR

TN

ch

r14:

7482

4617

R

SV

GC

G

42

0

32

0 49

18

F

ram

e sh

ift

- -

-


30

Abb

revi

atio

n: D

SV, d

iagn

osis

-spe

cific

var

iant

; D

RSV

, dia

gnos

is a

nd r

elap

se s

hare

d va

rian

t; R

SV, r

elap

se-s

peci

fic v

aria

nt.

AL

L-0

57

C19

orf5

1 ch

r19:

5567

2065

R

SV

C

- 33

0

54

0 60

12

F

ram

e sh

ift

- -

-

AL

L-0

57

KIF

6 ch

r6:3

9580

999

RSV

A

-

75

0 37

0

135

15

Fra

me

shif

t -

- -

AL

L-0

57

TE

AD

2 ch

r19:

4985

0472

R

SV

TG

T 16

4 0

85

0 22

3 59

F

ram

e sh

ift

- -

-

AL

L-0

58

KR

T1

chr1

2:53

0692

22

DR

SV

CA

CC

TC

CG

G

AG

CC

GT

A

GC

TG

CT

C

30

13

10

0 29

11

C

oden

del

etio

n p.

SSYG

S G

GG

557G

- -

AL

L-0

58

TM

EM

163

chr2

:135

2156

72

RSV

G

AG

TC

ATG

C

TT

GA

AC

A

CT

T G

70

0

41

0 40

13

C

oden

del

etio

n p.

EV

FK

H

DS2

41A

- -

AL

L-0

59

NC

OA

3 ch

r20:

4627

9818

D

RSV

G

CA

GC

AG

C

AG

CA

GC

A

GC

AA

G

47

12

32

0

54

21

Cod

en d

elet

ion

p.Q

QQ

QQ

Q

Q12

44Q

- -

AL

L-0

61

TC

HH

ch

r1:1

5208

4175

R

SV

T TT

GC

TG

C

TC

GC

G

CC

TC

TC

C12

1 0

26

0 85

24

C

odon

inse

rtio

n p.

Q50

6RR

G

ASS

K

- -

AL

L-0

62

NB

EA

L1

chr2

:203

9749

71

DR

SV

T TG

A

27

7 16

3 0

46

16

Fra

me

shif

t -

- -

AL

L-0

62

NR

3C1

chr5

:142

7800

58

RSV

T

TC

61

0

90

0 63

21

F

ram

e sh

ift

- -

-

AL

L-0

62

SFR

S15

chr2

1:33

0689

76

RSV

C

TG

TC

GTG

-

84

0 38

1

44

21

Fra

me

shif

t -

- -

AL

L-0

63

ZN

F23

6 ch

r18:

7461

7368

D

RSV

A

A

GC

C

104

30

46

0 75

24

C

odon

inse

rtio

n p.

H76

3QP

-

-

AL

L-0

63

MG

A

chr1

5:41

9888

16

DR

SV

T T

C

14

7 10

0 0

18

12

Fra

me

shif

t -

- -

AL

L-0

63

YP

EL

5 ch

r2:3

0381

654

RSV

C

T

C

137

0 54

0

84

22

Fra

me

shif

t -

- -

AL

L-0

64

DID

O1

chr2

0:61

5424

52

DR

SV

C

CT

26

9

18

0 28

8

Fra

me

shif

t -

- -

AL

L-0

64

RP

L5

chr1

:932

9911

9 R

SV

T T

A

102

0 96

0

109

29

Fra

me

shif

t -

- -

AL

L-0

66

NO

TC

H1

chr9

:139

3909

58

DR

SV

TGG

CG

G

CTG

CA

GG

-

6 3

10

0 9

3 F

ram

e sh

ift

- -

-

AL

L-0

76

SET

D2

chr3

:470

9890

7 D

SV

T T

C

61

17

32

0 49

0

Fra

me

shif

t -

- -

AL

L-0

76

AT

XN

1 ch

r6:1

6327

915

RSV

A

TG

C

A

13

0 10

0

17

8 C

oden

del

etio

n p.

QH

208H

-

-


31

Supplementary Table 3. Summary of somatic mutations in the 15 paired diagnosis and relapse samples

DSV DRSV RSV Total

Mutations

Missense/Gene 26/25 103/102 182/178 311/301

Nonsense/Gene 0/0 6/6 10/10 16/16

Splice site/Gene 1/1 7/7 7/7 15/15

Indels

Frame shift/Gene 2/2 6/6 11/11 19/19

Coden Insertion & deletion/Gene 2/2 3/3 7/7 12/11

Total/Gene 31/30 125/123 217/211 373/356

Abbreviation: DSV, diagnosis-specific variant; DRSV, diagnosis and relapse shared variant; RSV, relapse-specific variant.


32

Supplementary Table 4. SNVs correlation between whole-exome sequencing and microarray array

Sample ID

Total Affy SNP number in capture

region

Detected in Affy

6.0 Array

Detected in Seq.

(depth>1)

Consistent with Chip (depth>1)

Percentage (depth>1)

Detected in Seq.

Depth >8

Consistent with Chip

(depth>8)

Percentage (depth>8)

ALL-058-D 9,959 9,689 9,620 9,286 96.5% 8,575 8,388 97.8%

ALL-058-CR 9,959 9,247 9,224 7,866 85.3% 8,844 7,578 85.7%

ALL-058-R 9,959 9,602 9,544 9,055 94.9% 8,423 8,117 96.4%

ALL-059-D 9,959 9,808 9,715 9,405 96.8% 8,455 8,317 98.4%

ALL-059-CR 9,959 9,790 9,750 9,578 98.2% 8,892 8,817 99.2%

ALL-059-R 9,959 9,612 9,570 9,075 94.8% 8,551 8,229 96.2%

ALL-061-D 9,959 9,870 9,377 8,922 95.1% 6,776 6,714 99.1%

ALL-061-CR 9,959 9,450 9,421 8,605 91.3% 8,821 8,097 91.8%

ALL-061-R 9,959 9,601 9,592 9,245 96.4% 9,472 9,174 96.9%

ALL-063-D 9,959 9,876 9,859 9,761 99.0% 9,351 9,303 99.5%

ALL-063-CR 9,959 9,887 9,861 9,755 98.9% 9,282 9,232 99.5%

ALL-063-R 9,959 9,700 9,673 9,493 98.1% 9,127 9,020 98.8%

ALL-057-D 9,959 9,864 9,850 9,736 98.8% 9,494 9,409 99.1%

ALL-057-CR ND ND ND ND ND ND ND ND

ALL-057-R 9,959 9,836 9,824 9,688 98.6% 9,509 9,397 98.8%

ALL-062-D 9,959 9,843 9,823 9,739 99.1% 9,409 9,360 99.5%

ALL-062-CR 9,959 9,534 9,517 8,818 92.7% 9,275 8,614 92.9%

ALL-062-R 9,959 9,745 9,722 9,608 98.8% 9,257 9,190 99.3%

ALL-076-D 13,439 13,244 13,210 13,093 99.1% 12,748 12,678 99.5%

ALL-076-CR 13,439 13,370 13,329 13,180 98.9% 12,612 12,539 99.4%

ALL-076-R 13,439 13,273 13,241 13,092 98.9% 12,653 12,563 99.3%

ALL-024-D 13,439 13,313 13,275 13,167 99.2% 12,838 12,770 99.5%

ALL-024-CR 13,439 13,330 13,272 13,136 99.0% 12,534 12,478 99.6%

ALL-024-R 13,439 12,912 12,865 12,580 97.8% 12,097 11,889 98.3%

ALL-065-D 13,439 13,226 13,190 13,041 98.9% 12,537 12,464 99.4%

ALL-065-CR 13,439 13,360 13,325 13,192 99.0% 12,651 12,592 99.5%

ALL-065-R 13,439 13,204 13,179 13,040 98.9% 12,670 12,593 99.4%

ALL-023-D 13,439 13,277 13,193 12,934 98.0% 11,636 11,532 99.1%

ALL-023-CR 13,439 13,355 13,274 13,021 98.1% 11,811 11,722 99.2%

ALL-023-R 13,439 12,951 12,856 12,431 96.7% 11,361 11,110 97.8%

ALL-004-D 13,439 13,289 13,243 13,035 98.4% 12,454 12,352 99.2%

ALL-004-CR 13,439 13,289 13,260 13,136 99.1% 12,777 12,724 99.6%

ALL-004-R 13,439 13,075 13,021 12,789 98.2% 12,247 12,108 98.9%

ALL-039-D 13,439 13,305 13,276 13,150 99.1% 12,778 12,711 99.5%

ALL-039-CR 13,439 13,181 13,123 12,909 98.4% 12,158 12,063 99.2%

ALL-039-R 13,439 13,145 13,113 12,863 98.1% 12,620 12,441 98.6%

ALL-067-D 13,439 13,274 13,230 13,061 98.7% 12,555 12,464 99.3%

ALL-067-CR 13,439 13,303 13,206 12,908 97.7% 11,596 11,490 99.1%

ALL-067-R 13,439 12,957 12,922 12,641 97.8% 12,450 12,239 98.3%

ALL-064-D 13,439 13,265 13,188 12,931 98.1% 11,727 11,633 99.2%


33

ALL-064-CR 13,439 13,338 13,295 13,121 98.7% 12,587 12,512 99.4%

ALL-064-R 13,439 13,195 13,148 12,933 98.4% 12,333 12,209 99.0%

ALL-066-D 13,439 13,311 13,236 13,044 98.5% 12,176 12,085 99.3%

ALL-066-CR 13,439 13,339 13,282 13,091 98.6% 12,299 12,210 99.3%

ALL-066-R 13,439 13,164 13,135 12,999 99.0% 12,746 12,657 99.3%

Abbreviation: ND, No data. * Captured by using SureSelect Human All Exon 38Mb kit. Others using 50Mb kit.


34

Supplementary Table 5. Somatic copy number alterations

Sample ID Chromosome Start* End* Copy

Number※ CytoBand Diagnosis Relapse

ALL-004 chr1 149733376 248908210 3 q21.2-q44 + -

ALL-004 chr1 149733376 226933377 3 q21.2-q42.12 - +

ALL-004 chr5 10001 180667394 3 p15.33-q35.3 + +

ALL-004 chr6 60001 171055000 3 p25.3-q27 + +

ALL-004 chr7 50411582 50486820 1 7p12.2 + +

ALL-004 chr10 110000 135150010 3 p15.3-q26.3 + +

ALL-004 chr11 60001 134894790 3 p15.5-q25 + +

ALL-004 chr16 70442499 90052499 1 q22.1-q24.3 + -

ALL-004 chr18 60000 77999009 3 p11.32-q23 + +

ALL-004 chr21 14338130 47975572 3 q11.2-q22.3 + +

ALL-004 chr22 17220000 51244566 3 q11.1-q13.33 + +

ALL-023 chr2 89118885 89538885 1 p11.2 + +

ALL-023 chr6 70643279 107893307 1 q13-q21 + +

ALL-023 chr9 20000 20310000 1 p24.3-p21.3 + +

ALL-023 chr9 20410000 22510000 0 p21.3 + +

ALL-023 chr9 22510000 39310000 1 p21.3-p13.1 + +

ALL-023 chr12 145740 7508733 1 p13.33-p13.31 + +

ALL-023 chr12 17308733 34108733 1 p12.3-p11.1 + +

ALL-023 chr17 100000 18859275 1 p13.3-p11.2 - +

ALL-023 chr17 18859275 80706711 1 p11.2-q25.3 - +

ALL-023 chr22 23050000 23270000 1 q11.22 - +

ALL-024 chr1 145288643 145788643 1 q21.1 + +

ALL-024 chr1 146958376 147108376 1 q21.1-q21.2 + +

ALL-024 chr1 148533376 149383376 1 q21.2 + -

ALL-024 chr1 149733376 150733376 3 q21.2-q21.3 + -

ALL-024 chr1 150933376 152533376 3 q21.3 + -

ALL-024 chr2 89118885 89318885 1 p11.2 - +

ALL-024 chr6 101993307 103043307 1 q16.3 + -

ALL-024 chr6 136528307 148758307 1 q23.3-q24.3 + -

ALL-024 chr6 157712662 158580012 1 q25.3 + -

ALL-024 chr6 159480012 160680010 1 q25.3 + -

ALL-024 chr6 162280010 165080010 1 q26-q27 + -

ALL-024 chr8 15925629 16125629 1 p22 - +

ALL-024 chr9 6410000 8860000 1 p24.1 + -

ALL-024 chr9 10210000 14310000 1 p23-p22.3 + -

ALL-024 chr9 17210000 17310000 1 p22.2 + -

ALL-024 chr9 17310000 18510000 0 p22.2-p22.1 + -

ALL-024 chr9 18510000 20610000 1 p21.1-p21.3 + -

ALL-024 chr9 18760000 21310000 1 p22.1-p21.3 - +

ALL-024 chr9 20610000 20810000 0 p21.3 + -

ALL-024 chr9 20810000 21210000 1 p21.3 + -

ALL-024 chr9 21210000 22410000 0 p21.3 + -


35

ALL-024 chr9 21310000 22610000 0 p21.3 - +

ALL-024 chr9 22410000 24760000 1 p21.3 + -

ALL-024 chr9 22610000 25210000 1 p21.3 - +

ALL-024 chr9 24760000 25710000 0 p21.3-p21.2 + -

ALL-024 chr9 25710000 30610000 1 p21.2-p21.1 + -

ALL-024 chr9 25980000 26610000 1 p21.2 - +

ALL-024 chr9 30810000 31660000 1 p21.1 + -

ALL-024 chr9 32410000 33510000 1 p21.1-p13.3 + -

ALL-024 chr22 22370000 23220000 1 q11.22 - +

ALL-039 chr2 89118885 90062695 1 p11.2 + -

ALL-039 chr7 38296994 38390350 1 p14.1 + -

ALL-039 chr8 59979315 60701500 1 q12.1 + -

ALL-039 chr9 19410000 21210000 1 p22.1-p21.3 + -

ALL-039 chr9 19410000 22310000 1 p22.1-p21.3 - +

ALL-039 chr9 21210000 22170000 0 p21.3 + -

ALL-039 chr9 22170000 22310000 1 p21.3 + -

ALL-039 chr14 22200160 23030160 1 q11.2 - +

ALL-039 chr14 22200160 22830160 1 q11.2 + -

ALL-039 chr14 22830160 23030160 0 q11.2 + -

ALL-039 chr14 54430250 104828955 1 q22.2-q32.33 - +

ALL-039 chr18 210000 7910000 3 p11.32-p11.23 - +

ALL-058 chr2 89140113 89564733 1 2p11.2 + +

ALL-058 chr5 138161915 157642959 3 q31.2-q33.3 + +

ALL-058 chr5 158037422 158117422 3 q33.3 + -

ALL-058 chr5 158707422 158867422 3 q33.3 + +

ALL-058 chr5 159847422 160167422 3 q33.3-q34 + +

ALL-058 chr5 163567422 163937422 1 q34 + +

ALL-058 chr5 175067394 179267394 3 q35.2-q35.3 + +

ALL-058 chr5 179797394 180667394 1 q35.3 + +

ALL-058 chr7 6868475 7073475 3 p22.1 + -

ALL-058 chr7 20183475 20433475 3 7p15.3 + +

ALL-058 chr7 21543475 38319798 1 p15.3-p14.1 + +

ALL-058 chr7 38319798 38358475 0 p14.1 + +

ALL-058 chr7 38433475 51582506 1 p14.1-7p12.1 + +

ALL-058 chr7 63802565 64022565 1 q11.21 + +

ALL-058 chr7 71162064 72462064 3 q11.22-q11.23 + +

ALL-058 chr7 75162064 92612064 3 q11.23-q21.2 + +

ALL-058 chr7 93792064 93942064 3 q21.3 + +

ALL-058 chr7 100462064 100663280 1 q22.1 + +

ALL-058 chr7 101063280 111212764 3 q22.1-q31.1 + +

ALL-058 chr7 127462764 127912764 3 q32.1 + +

ALL-058 chr7 128812764 129112764 3 q32.1-q32.2 + +

ALL-058 chr7 129392764 131449460 3 q32.2-q32.3 + +

ALL-058 chr7 133849460 140753531 1 q33-q34 + +


36

ALL-058 chr7 142789878 147369067 1 q34-q35 + +

ALL-058 chr7 148619067 150169067 3 q36.1 + +

ALL-058 chr7 152369067 158707239 3 q36.2-q36.3 + +

ALL-058 chr9 21850000 21960000 1 p21.3 + +

ALL-058 chr9 21960000 22020000 0 p21.3 + +

ALL-058 chr9 22020000 22238000 1 p21.3 + -

ALL-058 chr10 59569994 59779994 1 q21.1 + +

ALL-058 chr14 106328955 107178955 1 q32.33 + +

ALL-058 chr20 43066586 53046593 1 q13.12-q13.2 + +

ALL-058 chr21 14978129 48119895 3 q11.2-q22.3 + -

ALL-061 chr1 189313377 189553377 1 q31.1 + +

ALL-061 chr2 89168885 89568885 1 p11.2 + +

ALL-061 chr7 50329454 50482506 1 p12.2 + +

ALL-061 chr9 21810000 21910000 1 p21.3 + -

ALL-061 chr9 21810000 22015383 1 p21.3 - +

ALL-061 chr9 21910000 22015383 0 p21.3 + -

ALL-061 chr9 36900000 37268871 1 p21.3 + +

ALL-061 chr10 42729994 43304994 1 q11.21 + +

ALL-061 chr14 106328955 107178955 1 q32.33 + +

ALL-062 chr5 717889 860215 3 p15.33 + +

ALL-062 chr9 10001 33010000 1 p24.3-p21.1 + +

ALL-062 chr10 60001 135524747 3 p15.3-q26.3 + +

ALL-062 chr11 129524790 129694790 3 q24.3 + +

ALL-062 chr14 22450160 22980160 1 q11.2 + -

ALL-062 chr14 22250160 22980160 1 q11.2 - +

ALL-062 chr16 32092499 33092499 1 p11.2 + +

ALL-062 chr18 7070000 7590000 3 p11.31-p11.23 + +

ALL-063 chr1 194703377 194853377 1 q31.3 - +

ALL-063 chr1 231458377 231633377 1 q42.2 + +

ALL-063 chr2 89118885 89598885 1 p11.2 + +

ALL-063 chr3 46474996 49524996 1 p21.31 - +

ALL-063 chr3 112057310 112237310 1 q13.2 + +

ALL-063 chr5 142619807 142789807 1 q31.3 - +

ALL-063 chr7 38282144 38399237 1 p14.1 + +

ALL-063 chr7 73802064 74212064 1 q11.23 + +

ALL-063 chr7 124012764 127412764 1 q31.33-q32.1 + +

ALL-063 chr7 142192444 142514878 1 q34 + +

ALL-063 chr7 143569067 143939067 1 q35 + +

ALL-063 chr7 144069067 149369067 1 q35-q36.1 + +

ALL-063 chr12 14508733 14658733 1 p13.1 + +

ALL-063 chr14 22865160 22990160 1 q11.2 + +

ALL-063 chr14 106878955 107218955 1 q32.33 + +

ALL-063 chr19 36908160 37038160 1 q13.12 + +

ALL-063 chr22 22390000 22610000 1 q11.22 + +


37

ALL-064 chr9 10001 39010000 1 p24.3-p13.1 + +

ALL-064 chr9 70910180 140880179 3 q21.11-q34.3 + -

ALL-064 chr9 70910180 95960179 3 q21.11-q22.31 - +

ALL-064 chr9 95960179 140880179 1 q22.31-q34.3 - +

ALL-064 chr10 89310020 89610020 1 q23.2-q23.31 + +

ALL-064 chr10 89610020 90060020 0 q23.31 + +

ALL-064 chr10 90060020 90710020 1 q23.31 + +

ALL-064 chr10 97710010 99510010 1 q24.1-q24.2 + +

ALL-064 chr14 22160160 22643365 1 q11.2 + +

ALL-064 chr14 22643365 23030160 0 q11.2 + +

ALL-065 chr2 89148885 89618885 1 p11.2 + -

ALL-065 chr4 173863425 175013425 1 q34.1 + -

ALL-065 chr7 38287975 38351019 1 p14.1 + -

ALL-065 chr7 50339454 50482506 1 p12.2 + -

ALL-065 chr9 19410000 21820000 1 p22.1-p21.3 + -

ALL-065 chr9 19410000 44060004 1 p22.1-p11.2 - +

ALL-065 chr9 21820000 22060000 0 p21.3 + -

ALL-065 chr9 22060000 44060004 1 p21.3-p11.2 + -

ALL-066 chr9 10001 21810000 1 p24.3-p21.3 + +

ALL-066 chr9 21810000 22015383 0 p21.3 + +

ALL-066 chr9 22015383 39010000 1 p21.3-p13.1 + +

ALL-066 chr14 22480160 22980160 1 q11.2 + +

ALL-067 chr2 89118885 89618885 1 p11.2 + +

ALL-067 chr7 10239 38233475 1 p22.3-p14.1 + +

ALL-067 chr7 38283475 38433475 0 p14.1 + +

ALL-067 chr7 38433475 159128663 1 p14.1-q36.3 + +

ALL-067 chr14 106128955 107108955 1 q32.33 + +

ALL-076 chr5 173947394 174107394 3 q35.2 - +

ALL-076 chr9 10001 38610000 1 p24.3-p13.2 + +

ALL-076 chr9 130500179 130680179 1 q34.11 - +

ALL-076 chr9 133510179 141080179 3 q34.12-q34.3 + +

ALL-076 chr14 106428955 107138955 1 q32.33 + +

ALL-076 chr21 14338130 48119895 3 q11.2-q22.3 + +

ALL-076 chr22 16870000 23670000 3 q11.1-q11.23 + +

*Based on hg 19 ※Copy number > 2 represents amplification, < 2 deletion.


38

Supplementary Table 6. Distributions of copy number variants

Mutation spectrum

Copy number alterations(CNA)

DSV DRSV RSV

ALL-004 2 8 1

ALL-023 0 7 3

ALL-024 21 2 7

ALL-039 8 0 4

ALL-057 ND ND ND

ALL-058 4 29 0

ALL-059 0 0 0

ALL-061 2 6 1

ALL-062 1 6 1

ALL-063 0 13 4

ALL-064 1 7 2

ALL-065 7 0 1

ALL-066 0 4 0

ALL-067 0 5 0

ALL-076 0 5 2

Total 46 92 26

Abbreviation: DSV, diagnosis-specific variant; DRSV, diagnosis and relapse shared variant; RSV, relapse-specific variant. ND, No data.


39

Supplementary Table 7 Characteristics of children with relapsed ALL

a. Characteristics of 144 cases of children with relapsed ALL in Chinese cohort

Patient ID

Age at diagnosis

(year) Sex

WBC (×109/L)

Cytogenetics Immunophenotype

BM Blast at diagnosis

(%)&

BM Blast at relapse (%)&

Time interval

(Month)¶ ALL-001 10.41 Female 2.0 Normal B 38.0% 65.6% 19.0 ALL-002 2.65 Female 3.3 -19 B 97.2% 95.1% 86.0 ALL-003 7.20 Male 64.3 Normal T 96.0% 34.8% 25.8 ALL-005 5.00 Female 74.0 t(9;22) B 84.8% 96.4% 14.1 ALL-006 3.15 Male 32.7 Normal B 90.0% 82.4% 19.5 ALL-007 3.71 Male 65.5 Failed B 89.0% 95.2% 42.1 ALL-008 4.79 Male 45.5 Failed B 89.2% 41.2% 9.8 ALL-009 6.41 Male 3.2 Normal B 58.8% 98.8% 3.7 ALL-010 11.04 Female 64.5 Normal B 97.2% 92.8% 12.3 ALL-011 8.95 Male 455.0 Normal B 96.8% 83.6% 32.1 ALL-012 12.59 Female 123.0 Failed B 94.0% 37.6% 52.5 ALL-013 14.90 Male 4.7 t(12;21) B 95.6% 82.0% 38.8 ALL-014 2.80 Female 4.7 Normal B 92.4% 94.0% 49.7 ALL-015 7.16 Male 14.3 t(9;22) B 85.2% 81.2% 88.9 ALL-016 10.68 Female 22.3 Failed B 98.4% 98.8% 17.0 ALL-017 2.60 Female 5.3 Normal B 79.2% 68.8% 7.5 ALL-018 3.13 Female 0.5 Normal B 98.4% 69.6% 4.5 ALL-019 5.61 Female 13.5 Normal B 95.1% 94.8% 59.0 ALL-020 2.53 Female 15.5 Normal B 72.0% 91.2% 22.3 ALL-021 11.68 Male 11.7 t(9;22) B 92.0% 94.4% 42.3 ALL-022 4.88 Male 22.7 Normal B 94.4% 56.4% 43.1 ALL-025 10.63 Female 5.3 t(9;22) B 64.4% 89.1% 12.7 ALL-026 3.62 Male 228.0 t(9;22) B 89.0% 56.8% 3.7 ALL-027 6.82 Male 3.3 Normal B 96.0% 93.1% 91.1 ALL-028 11.64 Female 192.1 Normal B 93.6% 30.0% 32.6 ALL-029 14.55 Male 23.7 t(1;19) B 96.4% 95.6% 9.7 ALL-030 2.19 Male 4.2 Failed B 93.6% 60.8% 19.5 ALL-031 5.96 Female 15.1 Failed B 64.2% 98.8% 26.6 ALL-032 9.67 Female 23.9 Normal B 82.8% 50.4% 12.2 ALL-033 8.39 Female 24.8 Failed B 88.4% 40.8% 11.2 ALL-034 4.69 Male 6.8 Normal B 90.8% 92.4% 22.7 ALL-035 3.55 Female 2.8 Normal B 33.0% 86.8% 8.9 ALL-036 8.45 Male 189.3 Failed B 95.2% 82.0% 12.5 ALL-037 3.52 Male 21.4 Normal B 94.0% 33.4% 19.7 ALL-038 0.88 Male 2.1 Normal B 81.2% 93.6% 15.7 ALL-040 1.90 Male 4.7 Normal B 84.4% 99.2% 51.4 ALL-041 2.22 Female 30.7 Failed B 94.8% 96.8% 72.1 ALL-042 4.08 Male 6.4 Normal B 93.2% 96.8% 74.8 ALL-043 3.33 Male 7.5 Normal B 97.2% 50.0% 26.3 ALL-044 6.57 Male 105.5 t(1;19) B 94.0% 98.8% 12.7 ALL-045 5.51 Male 4.8 t(9;22) B 96.0% 83.6% 10.6 ALL-046 2.55 Male 1.1 Failed B 97.5% 75.0% 39.0 ALL-047 1.17 Female 12.1 Failed B 31.0% 98.0% 126.8 ALL-048 7.37 Male 65.8 Failed B 64.4% 96.8% 57.8 ALL-049 6.79 Male 4.9 Normal B 69.6% 70.8% 75.9

ALL-050 11.17 Male 24.6 Complex [no favorable]

T 77.6% 89.6% 3.0

ALL-051 6.30 Female 36.3 t(12;21) B 99.2% 99.2% 38.1 ALL-052 8.65 Male 4.2 Failed B 45.0% 99.2% 18.4 ALL-053 12.19 Male 185.0 Normal B 98.0% 83.2% 57.0 ALL-054 12.72 Female 26.8 t(9;22) B 94.4% 62.8% 4.9 ALL-055 3.81 Male 26.7 t(12;21) B 90.4% 96.0% 41.2 ALL-056 12.90 Male 274.6 t(9;22) B 50.0% 94.2% 4.5 ALL-068 2.24 Male 13.0 Normal B 91.6% 94.8% 19.3 ALL-069 15.02 Female 9.2 t(9;22) B 88.0% 94.8% 9.9 ALL-070 8.75 Male 50.4 Normal B 94.4% 78.8% 29.7 ALL-071 12.78 Male 43.3 Normal B 96.4% 96.8% 17.3 ALL-072 4.06 Male 9.0 Normal T 25.0% 68.0% 12.5 ALL-073 4.64 Female 42.3 t(1,19) B 91.8% 64.4% 64.4

ALL-074 1.03 Female 18.7 Complex [no favorable]

B 85.6% 52.8% 11.3

ALL-075 4.37 Female 175.8 Failed B 45.0% 93.6% 8.9 ALL-077 8.01 Male 7.2 -3 B 85.0% 58.8% 57.0 ALL-078 0.68 Male 2.9 Normal B 56.8% 26.4% 44.8 ALL-079 10.05 Male 6.2 Normal B 91.6% 89.3% 50.6 ALL-080 3.96 Male 20.9 t(12;21) B 98.4% 89.2% 41.3 ALL-081 2.90 Male 7.6 +18 B 90.4% 80.4% 37.4 ALL-082 6.94 Male 1.9 t(12;21) B 98.0% 45.6% 42.5 ALL-083 3.42 Male 36.6 t(12;21) B 94.4% 99.6% 10.3


40

ALL-084 2.66 Female 14.8 t(12;21) B 94.0% 92.8% 38.4 ALL-085 9.26 Male 177.7 Normal B 82.0% 73.6% 19.3 ALL-086 3.94 Male 119.8 t(12;21) B 98.4% 88.6% 15.3 ALL-087 10.85 Male 138.2 Normal B 92.0% 92.8% 18.7 ALL-088 14.96 Male 145.4 Failed B 93.6% 45.6% 18.7 ALL-089 2.58 Male 22.9 +1p; -8 T 94.4% 80.8% 4.0 ALL-090 3.55 Male 37.0 Failed B 71.6% 94.8% 29.3 ALL-091 0.75 Male 76.1 Normal B 96.4% 92.4% 5.7 ALL-092 7.25 Male 10.5 Failed B 91.6% 95.6% 37.7 ALL-093 0.23 Female 32.6 Normal B 90.0% 83.0% 2.7 ALL-094 3.75 Male 4.5 Normal B 97.2% 90.0% 37.6 ALL-095 12.22 Male 103.2 +8 T 96.0% 82.0% 3.0 ALL-096 7.77 Male 8.3 Failed B 41.6% 92.0% 17.6 ALL-097 4.16 Female 3.7 Normal B 32.3% 98.4% 43.3 ALL-098 13.88 Male 77.0 Normal T 37.8% 52.0% 6.5 ALL-099 14.21 Male 22.6 Normal B 92.4% 78.0% 12.5 ALL-100 2.15 Male 24.9 t(9;22) B 96.0% 51.6% 22.3 ALL-101 9.95 Male 41.8 Normal T 90.4% 87.0% 27.9 ALL-102 6.08 Female 99.1 Normal B 95.6% 74.0% 31.2 ALL-103 9.81 Male 22.5 Failed B 78.4% 50.0% 32.4 ALL-104 7.41 Female 1.9 Normal T 64.0% 73.2% 76.9 ALL-105 11.53 Male 42.7 Normal T 87.6% 85.0% 8.6 ALL-106 4.40 Female 5.4 t(9;22) B 73.6% 82.8% 3.2 ALL-107 2.73 Male 3.0 Normal B 89.4% 94.0% 48.6 ALL-108 11.62 Male 11.0 Normal T 88.4% 62.4% 42.5 ALL-109 12.21 Male 16.4 t(9;22) B 96.8% 60.0% 3.8 ALL-110 3.67 Male 9.0 Normal B 89.0% 89.6% 61.6 ALL-111 5.44 Female 3.2 Normal B 97.0% 98.0% 31.6 ALL-112 4.43 Male 157.6 del(6)(q24) T 91.6% 76.8% 10.9 ALL-113 13.62 Male 4.4 Failed B 57.6% 79.6% 84.5 ALL-114 4.10 Female 1.8 Normal B 90.8% 92.0% 47.4 ALL-115 14.58 Female 52.5 Failed B 90.1% 36.8% 14.8 ALL-116 3.52 Male 1392.0 t(9;22) B 91.2% 91.2% 16.0 ALL-117 4.48 Male 31.5 +14,-16 B 89.6% 81.5% 11.4 ALL-118 4.46 Male 15.0 t(1;19) B 92.8% 76.0% 7.1 ALL-119 8.24 Female 30.8 t(9;22) B 95.6% 60.8% 3.8 ALL-120 7.21 Male 14.9 Normal B 90.4% 93.2% 9.9 ALL-121 15.13 Female 2.0 Failed B 84.4% 84.8% 16.0

ALL-122 2.40 Female 20.5 Hyperdiploid

(54~55) B 95.2% 86.4% 36.0

ALL-123 2.35 Male 100.0 Failed T 84.5% 92.8% 6.1 ALL-124 6.72 Female 52.6 Normal B 89.2% 90.4% 86.0 ALL-125 3.13 Male 18.8 Normal B 89.6% 90.8% 29.8 ALL-126 3.38 Female 3.5 +8; -21; -14 B 93.6% 84.4% 33.5 ALL-127 1.96 Male 2.0 Failed T 95.2% 94.4% 18.7

ALL-128 4.20 Male 47.1 Hyperdiploid

(46~57) B 97.2% 38.4% 11.0

ALL-129 4.20 Female 6.5 Normal B 95.6% 40.0% 14.7 ALL-130 7.19 Female 30.5 Failed B 88.4% 89.2% 22.5

ALL-131 6.39 Male 9.3 t(3;14);t(2;8);t

(8;22)B 81.6% 90.8% 45.0

ALL-132 10.00 Male 81.8 t(1,15) T 92.6% 89.6% 18.9 ALL-133 1.85 Female 4.4 Normal B 96.8% 72.0% 20.0 ALL-134 4.46 Male 1.7 2p- B 78.4% 40.8% 14.4 ALL-135 5.11 Male 39.7 t(14;15) B 92.8% 35.2% 4.6 ALL-136 11.19 Male 1122.6 t(9;22) B 89.6% 76.4% 37.5 ALL-137 9.98 Male 2.8 Normal B 91.6% 33.2% 32.6 ALL-138 10.62 Male 92.5 Failed T 92.4% 93.2% 17.0 ALL-139 3.65 Female 3.3 Failed B 96.4% 58.8% 11.0 ALL-140 2.18 Male 170.3 Failed T 87.2% 56.0% 2.4 ALL-141 12.54 Female 14.4 Normal B 84.8% 96.8% 9.3 ALL-142 6.58 Male 26.4 -1; 1p+; 1q- B 86.8% 89.2% 13.5 ALL-143 4.22 Female 6.9 Normal B 82.8% 54.4% 12.2 ALL-144 6.45 Male 2.1 Normal B 87.2% 49.2% 41.6 ALL-145 11.46 Male 1167.0 Normal B 90.0% 90.4% 16.7 ALL-146 6.84 Male 5.5 Failed B 96.4% 90.8% 35.1 ALL-147 12.17 Female 141.7 +8 B 96.0% 84.4% 10.3 ALL-148 1.05 Female 31.0 Failed B 90.0% 68.8% 11.0 ALL-149 2.55 Male 1.1 Failed B 97.5% 90.8% 39.0 ALL-150 13.17 Male 4.0 t(9;22) B 64.5% 92.4% 12.1 ALL-151 12.19 Male 5.8 t(9;22) B 93.6% 67.6% 11.0 ALL-152 12.36 Male 104.5 t(9;22) B 93.6% 44.4% 10.8 ALL-153 5.68 Female 54.1 Failed B 84.5% 84.4% 24.5 ALL-154 6.19 Male 377.0 Normal T 90.4% 78.0% 3.9 ALL-155 5.92 Male 82.6 Normal B 94.8% 90.0% 32.6 ALL-156 7.38 Male 4.7 Failed B 53.6% 98.0% 19.2


41

ALL-157 10.63 Female 163.0 Failed B 85.0% 45.2% 11.3 ALL-158 3.65 Male 17.6 Normal B 98.8% 98.0% 24.5 ALL-159 0.84 Male 24.9 Normal B 94.8% 87.6% 24.3 ALL-160 8.54 Female 61.2 Normal B 93.6% 97.2% 8.3

& BM blast ratio at diagnosis and relapse were identified by bone marrow morphology observe. ¶ Months elapsed from diagnosis to relapse. b. Characteristics of 220 German cases with relapsed B-ALL

Patient ID

Age at diagnosis

(years) Sex

WBC (×109/L)

Fusion genes¥

Immunophenotype relapse sample from

relapse sample blast (%)&

Time interval

(months)¶

ALL-201 4.92 male 4.1 negative pre B ALL BM 94 67.83

ALL-202 3.10 female 17.5 negative common ALL BM 98 35.70

ALL-203 0.34 male 32.9 MLL-AFF1 pro B ALL BM 63 12.43


ALL-206 2.57 female 9.7 negative pre B ALL BM 89 27.63

ALL-207 13.40 male 154.0 MLL-AFF1 precursor B-ALL, n. s. BM 98 8.90


ALL-208 5.26 male 7.4 ETV6-RUNX1 common ALL BM 84 49.67


ALL-211 0.75 female 131.0 negative pro B ALL BM 89 9.60

ALL-215 7.47 female 2.9 ETV6-RUNX1 common ALL BM 98 37.10

ALL-213 10.71 male 25.7 negative common ALL BM 89 14.67





ALL-216 8.85 male 5.1 ETV6-RUNX1 pre B ALL BM 36 37.53







ALL-227 7.20 female 8.7 E2A-PBX1 common ALL BM 62 33.37



ALL-225 2.87 male 9.2 negative pro B ALL BM 86 30.30









ALL-242 5.79 female 25.7 negative precursor B-ALL, n. s. BM 96 51.53


42














ALL-255 3.31 male -1.0 negative common ALL BM 86 14.43


ALL-256 1.56 male 13.7 negative precursor B-ALL, n. s. BM 67 26.20








ALL-262 4.24 male 9.7 negative common ALL pB 73 28.37





ALL-271 2.25 male 1.7 E2A-PBX1 precursor B-ALL, n. s. BM 54 32.73












ALL-283 12.04 female 50.0 negative common ALL pB 89 49.63


ALL-285 3.41 male 100.0 BCR-ABL1 pre B ALL pB 71 61.70

ALL-286 6.10 male 52.5 negative biphenotypic ALL BM 98 40.10



43







ALL-298 1.02 male 12.4 MLL-AFF1 pro B ALL BM 85 17.50


ALL-289 7.65 female 2.5 BCR-ABL1 common ALL BM 98 24.50






ALL-304 1.23 male 10.7 negative pre B ALL pB 71 24.90


















ALL-324 7.75 female 3.4 negative biphenotypic ALL BM 94 56.07



ALL-326 3.25 male 11.0 BCR-ABL1 common ALL BM 64 25.13






ALL-333 13.76 female 1.7 n. a. common ALL BM 50 38.60

ALL-336 12.61 female 3.6 MLL-AFF1 pro B ALL BM 90 20.33

ALL-337 4.01 female 11.0 ETV6-RUNX1 pre B ALL BM 99 38.23



44





ALL-343 10.94 female 216.0 E2A-PBX1 precursor B-ALL, n. s. BM 82 8.70













ALL-357 11.93 male 26.4 negative pre B ALL Testis n. a. 28.90












ALL-366 3.49 female 13.0 BCR-ABL1 common ALL BM 91 55.63








ALL-379 4.58 female 3.2 n. a. common ALL BM 95 18.53




ALL-382 3.95 male 2.9 n. a. common ALL BM 93 55.00





45






ALL-391 11.14 female 5.1 n. a. precursor B-ALL, n. s. BM 95 42.57






ALL-399 6.33 male 41.4 negative common ALL pB 80 103.30




























ALL-431 14.98 female 331.9 negative common ALL pB 96 50.80




ALL-433 11.68 female 3.9 ETV6-RUNX1 pre B ALL BM 73 38.80



46



ALL-437 1.40 male 40.1 negative precursor B-ALL, n. s. pB 88 39.83


¥Patients were analyzed by RT-PCR for presence of fusion genes ETV6-RUNX1, BCR-ABL1, MLL-AFF1, and E2A-PBX1, &blast percentage in relapse sample by morphology ¶months elapsed from diagnosis to relapse; Abbreviations: BM, bone marrow; pB, peripheral blood; n. a., not assessed; n. s., not specified

Supplementary Table 8. Summary of relapse-specific mutations in purine synthesis pathways


47

Annotated gene

Sample ID

Immuno- phenotype

Mutation type

Position Allele

change Amino acid

change Case number with mutation

Frequency(%)*

PRPS2 ALL-114 B Nonsyn. ChrX: 12,809,680 C>A R22S 1 2.8(3/107)

ALL-120 B Nonsyn. ChrX: 12,827,354 G>T S106I 1

ALL-127 T Nonsyn. ChrX: 12,828,244 C>G P173R 1

ATIC ALL-140 T Nonsyn. Chr2:216,190,755 T>C V142A 1 1.7(2/116)

ALL-114 B Nonsyn. Chr2:216,191,545 G>T A178S 1

ADSL ALL-060 T Nonsyn. Chr22:40,745,936 G>A R85Q 1 0.9(1/107)

GART ALL-056 B Nonsyn. Chr21:34,876,538 G>A V976I 2 1.9(2/105)

ALL-077 B Nonsyn. Chr21:34,876,538 G>A V976I

PFAS ALL-002 B Nonsyn. Chr17:8,170,084 T>A L945Q 1 1.3(1/81) * Limited by samples, which used for detecting to each gene are different. Except the genes list here, we also sequenced the whole exons of TPMT, HPRT1, PAICS, PPAT, NT5C2, however no obvious mutation was found. Supplementary Table 9. Summary of Vmax and Km values of wild-type, drug resistant and control mutant PRPS1 for substrates Ribose-5 Phosphate (R-5-P) and ATP, respectively


48

PRPS1 Km (M) Vmax (mol/min/mg)

R5P ATP R5P ATP

Control WT 76.83 45.75 25.85 22.65

Allosteric site

S103T 93.5 35.5 19.5 19.5 S103N 96 32 24.5 21

N144S 75 32 17 15 T303S 68 20 15 15

Dimer interface

K176N 42 18 9 7 D183E 68 23 13 15 A190T 114.7 80.67 10.8 11.9

A190V 222.3 73 16.9 16.1 L191F 333 22 6 5

Reduced function

A87T 72 28 17 19

M115T 73.33 47 16 16.3


49

Supplementary Table 10. Summary of IC50 values for ADP and GDP feedback inhibition of

wild-type, drug resistant or control PRPS1 mutants’s enzymatic activities

PRPS1

ADP GDP IC50 (M) Fold IC50 (M) Fold

Control WT 60 1.00 180 1.00

Allosteric site

S103T 370 6.17 >5000 >25 S103N 380 6.33 >5000 >25 N144S 290 4.83 >5000 >25 T303S 150 2.50 1306 7.26

Dimer interface

K176N 240 4.00 1016 5.64 D183E 170 2.83 645 3.58 A190T 163 2.72 4700 26.11 A190V 300 5.00 1151 6.39 L191F 450 7.50 2226 12.37

Reduced function

A87T 67 1.12 170 0.94 M115T 58 0.97 221 1.23


50

Supplementary Table 11. Primers for exons re-sequencing of PRPS1

Exon Primer (5’ to 3’) Fragmnet size Anneling

Temperature

1 TGAGTCTGTGGCCGACTTC 272bp 63℃

CGACCCCATCCCTCCTATAC

2 TCAATCCACACTTGGTTGAATC 568bp 63℃

TCCAGAGGAGTTGGTGCTTAG

3 ATGAATTTCTGGGTACCATAGTG 298bp 63℃

CTTCTCTGCAGTCTTCAGCATC

4 AATCTACCACACTGGGCCTG 400bp 63℃

CCATGTGCTAGCTACTTACATCC

5 CCCCGGCCTCTTTAGTCC 322bp 58℃

TCAGCAGGCTGAAGACATTC

6 GTTGTGGAAGCCTAAGCAGG 342bp 63℃

CTTCAGAATCCAGAGACCTAATTC

7a TCATGACAGGGAAACAGCAC 547bp 63℃

GAGCTTCCCCAGTCACAGTC

7b CTATAGCTCAGCTGCTGCAAG 832bp 58℃

CAATGGACAGCAAGACATCTATC


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Negative feedback-defective PRPS1 mutants drive … · Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL ... S1 03 24h Ve cto r W