Drug Information

Drug (ID: DG00134) and It's Reported Resistant Information
Name
Mercaptopurine
Synonyms
6-mercaptopurine; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptopurin; Mercaptopurina; Mercaptopurinum; Mercapurin; Merkaptopuryna; Mern; Purimethol; Purinethiol; Purinethol; Thiopurine; Leupu rin; Mercaptopurin [German]; Mercaptopurina Wellcome; Mercaptopurine anhydrous; Merkaptopuryna [Polish]; Puri Nethol; BW 57 323H; Glaxo Wellcome Brand of 6 Mercaptopurine; GlaxoSmithKline Brand of 6 Mercaptopurine; M0063; NCIMech_000025; PM6; Wellcome Brand of 6 Mercaptopurine; Glaxo Wellcome Brand of 6-Mercaptopurine; GlaxoSmithKline Brand of 6-Mercaptopurine; Mercaptopurina [INN-Spanish]; Mercaptopurine (INN); Mercaptopurine (VAN); Mercaptopurine (anhydrous); Mercaptopurinum [INN-Latin]; Puri-Nethol; Purineantimetabolite: inhibits nucleic acid replication; Purinethol (TN); U-4748; Wellcome Brand of 6-Mercaptopurine; AG-670/31547064; Purine-6-thiol; Leukerin, 99%-Carc; Purine-6(1H)-thione; Purinethol, 6-mercaptopurine, 6-MP, Mercaptopurine; 6 MP; 6 Mercaptopurine Monohydrate; 6 Thiohypoxanthine; 6 Thiopurine; 6-MERCAPTOPURINE MONOHYDRATE; 6-MP; 6-Mercaptopurin; 6-Merkaptopurin; 6-Merkaptopurin [Czech]; 6-Purinethiol; 6-Thiohypoxanthine; 6-Thiopurine; 6-Thioxopurine; Mercaptopurine (Purine analog)
    Click to Show/Hide
Indication
In total 2 Indication(s)
Mature B-cell lymphoma [ICD-11: 2A85]
Approved
[1]
Crohn disease [ICD-11: DD70]
Phase 4
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[2]
Acute myeloid leukemia [ICD-11: 2A60]
[3], [4]
Inflammatory bowel diseases [ICD-11: DD72]
[5]
Target Amidophosphoribosyltransferase (PPAT) PUR1_HUMAN [1]
Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1) IMDH1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C5H4N4S
IsoSMILES
C1=NC2=C(N1)C(=S)N=CN2
InChI
1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)
InChIKey
GLVAUDGFNGKCSF-UHFFFAOYSA-N
PubChem CID
667490
ChEBI ID
CHEBI:2208
TTD Drug ID
D09UZO
VARIDT ID
DR00145
INTEDE ID
DR1031
DrugBank ID
DB01033
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  DISM: Drug Inactivation by Structure Modification
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [3], [4]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.R238W (c.c712t)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5OPP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.84  Å
PDB: 5L4Z
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.41
TM score: 0.99758
Amino acid change:
R238W
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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60
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70
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90
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A
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F
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G
G
100
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L
L
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110
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L
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D
D
A
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G
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120
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C
C
A
A
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H
G
G
F
F
N
N
F
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130
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G
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140
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150
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160
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A
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170
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180
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190
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220
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230
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G
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240
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260
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270
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290
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310
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G
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G
320
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330
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G
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340
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410
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420
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440
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450
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F
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D
460
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Y
A
A
A
A
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F
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N
L
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L
470
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Y
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Y
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A
480
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A
A
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490
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N
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500
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M
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Acute lymphocytic leukemia [ICD-11: 2B33]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [6]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.R367Q
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.30  Å
PDB: 6FXH
Mutant Type Structure Method: X-ray diffraction Resolution: 2.50  Å
PDB: 6DDK
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.64
TM score: 0.87692
Amino acid change:
R367Q
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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G
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M
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D
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L
10
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Q
N
N
A
A
A
A
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D
M
M
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A
A
N
N
M
M
20
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D
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H
A
A
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L
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K
K
K
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Y
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R
R
R
30
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E
E
A
A
Y
Y
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H
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R
V
V
F
F
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V
N
N
R
R
40
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S
L
L
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A
M
M
E
E
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K
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I
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K
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C
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F
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G
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F
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N
M
M
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D
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Y
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T
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L
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A
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V
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Y
Y
K
K
S
S
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P
E
E
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Y
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E
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S
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L
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G
70
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F
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E
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L
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T
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G
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F
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A
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Y
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G
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G
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N
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L
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L
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K
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V
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D
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A
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Y
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G
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N
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L
L
L
120
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V
V
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C
A
A
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H
G
G
F
F
N
N
F
F
I
I
R
R
130
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G
G
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P
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E
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T
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R
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E
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Y
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P
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N
140
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K
K
F
F
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I
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Q
R
R
D
D
D
D
T
T
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E
R
R
150
|
F
F
Y
Y
I
I
L
L
N
N
T
T
L
L
F
F
N
N
L
L
160
|
P
P
E
E
T
T
Y
Y
L
L
L
L
A
A
C
C
L
L
V
V
170
|
D
D
F
F
F
F
T
T
N
N
C
C
P
P
R
R
Y
Y
T
T
180
|
S
S
C
C
E
E
T
T
G
G
F
F
K
K
D
D
G
G
D
D
190
|
L
L
F
F
M
M
S
S
Y
Y
R
R
S
S
M
M
F
F
Q
Q
200
|
D
D
V
V
R
R
D
D
A
A
V
V
D
D
W
W
V
V
H
H
210
|
Y
Y
K
K
G
G
S
S
L
L
K
K
E
E
K
K
T
T
V
V
220
|
E
E
N
N
L
L
E
E
K
K
Y
Y
V
V
V
V
K
K
D
D
230
|
G
G
K
K
L
L
P
P
L
L
L
L
L
L
S
S
R
R
M
M
240
|
K
K
E
E
V
V
G
G
K
K
V
V
F
F
L
L
A
A
T
T
250
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N
N
S
S
D
D
Y
Y
K
K
Y
Y
T
T
D
D
K
K
I
I
260
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M
M
T
T
Y
Y
L
L
F
F
D
D
F
F
P
P
H
H
G
G
270
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P
P
K
K
P
P
G
G
S
S
S
S
H
H
R
R
P
P
W
W
280
|
Q
Q
S
S
Y
Y
F
F
D
D
L
L
I
I
L
L
V
V
D
D
290
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A
A
R
R
K
K
P
P
L
L
F
F
F
F
G
G
E
E
G
G
300
|
T
T
V
V
L
L
R
R
Q
Q
V
V
D
D
T
T
K
K
T
T
310
|
G
G
K
K
L
L
K
K
I
I
G
G
T
T
Y
Y
T
T
G
G
320
|
P
P
L
L
Q
Q
H
H
G
G
I
I
V
V
Y
Y
S
S
G
G
330
|
G
G
S
S
S
S
D
D
T
T
I
I
C
C
D
D
L
L
L
L
340
|
G
G
A
A
K
K
G
G
K
K
D
D
I
I
L
L
Y
Y
I
I
350
|
G
G
D
D
H
H
I
I
F
F
G
G
D
D
I
I
L
L
K
K
360
|
S
S
K
K
K
K
R
R
Q
Q
G
G
W
W
R
Q
T
T
F
F
370
|
L
L
V
V
I
I
P
P
E
E
L
L
A
A
Q
Q
E
E
L
L
380
|
H
H
V
V
W
W
T
T
D
D
K
K
S
S
S
S
L
L
F
F
390
|
E
E
E
E
L
L
Q
Q
S
S
L
L
D
D
I
I
F
F
L
L
400
|
A
A
E
E
L
L
Y
Y
K
K
H
H
L
L
D
D
S
S
S
S
410
|
S
S
N
N
E
E
R
R
P
P
D
D
I
I
S
S
S
S
I
I
420
|
Q
Q
R
R
R
R
I
I
K
K
K
K
V
V
T
T
H
H
D
D
430
|
M
M
D
D
M
M
C
C
Y
Y
G
G
M
M
M
M
G
G
S
S
440
|
L
L
F
F
R
R
S
S
G
G
S
S
R
R
Q
Q
T
T
L
L
450
|
F
F
A
A
S
S
Q
Q
V
V
M
M
R
R
Y
Y
A
A
D
D
460
|
L
L
Y
Y
A
A
A
A
S
S
F
F
I
I
N
N
L
L
L
L
470
|
Y
Y
Y
Y
P
P
F
F
S
S
Y
Y
L
L
F
F
R
R
A
A
480
|
A
A
H
H
V
V
L
L
M
M
P
P
H
H
E
E
S
S
T
T
490
|
V
V
E
E
H
H
T
T
H
H
V
V
D
D
I
I
N
N
E
E
500
|
M
M
E
E
S
S
P
P
L
L
A
A
T
T
R
R
N
N
R
R
510
|
T
T
S
S
V
V
D
D
F
F
K
K
D
D
T
T
D
D
Y
Y
520
|
K
K
R
R
H
H
Q
Q
L
L
T
T
R
R
S
S
I
I
S
S
530
|
E
E
I
I
K
K
P
P
P
P
N
N
L
L
F
F
P
P
L
L
540
|
A
A
P
P
Q
Q
E
E
I
I
T
T
H
H
C
C
H
H
D
D
550
|
E
E
D
D
D
D
D
D
E
E
E
E
E
E
E
E
E
E
E
E
560
|
E
E
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Exome sequencing assay
Experiment for
Drug Resistance		 Conality analyses assay
Mechanism Description These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.
References
Ref 1 The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia. Curr Opin Hematol. 2014 Jul;21(4):320-5. doi: 10.1097/MOH.0000000000000058.
Ref 2 Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood. 2008 Nov 15;112(10):4178-83. doi: 10.1182/blood-2008-06-165027. Epub 2008 Sep 2.
Ref 3 Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013 Mar;45(3):290-4. doi: 10.1038/ng.2558. Epub 2013 Feb 3.
Ref 4 The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-80. doi: 10.1182/asheducation-2014.1.174. Epub 2014 Nov 18.
Ref 5 Drug resistance in inflammatory bowel diseases .Curr Opin Pharmacol. 2015 Dec;25:56-61. doi: 10.1016/j.coph.2015.11.003. Epub 2015 Nov 29. 10.1016/j.coph.2015.11.003
Ref 6 Mutational profiling of acute lymphoblastic leukemia with testicular relapse. J Hematol Oncol. 2017 Mar 2;10(1):65. doi: 10.1186/s13045-017-0434-y.

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