Molecule Information

General Information of the Molecule (ID: Mol00006)
Name
Tyrosine-protein kinase ABL1 (ABL1) ,Homo sapiens
Synonyms
Abelson murine leukemia viral oncogene homolog 1; Abelson tyrosine-protein kinase 1; Proto-oncogene c-Abl; p150; ABL; JTK7
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Molecule Type
Protein
Gene Name
ABL1
Gene ID
25
Location
chr9:130713016-130887675[+]
Sequence
MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE
NDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVN
SLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTAS
DGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERT
DITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQ
LLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFI
HRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKS
DVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNP
SDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSRRAAE
HRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLF
SALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSP
KPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSAS
CVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTV
TPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGS
ALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPP
PPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPGEGLKKPVL
PATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPE
RIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNK
FAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR
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3D-structure
PDB ID
5MO4
Classification
Transferase
Method
X-ray diffraction
Resolution
2.17  Å
Function
Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717'. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21-dependent manner. Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity.
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Uniprot ID
ABL1_HUMAN
Ensembl ID
ENSG00000097007
HGNC ID
HGNC:76
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
5 drug(s) in total
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Axitinib
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I (c.944C>T)
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Mechanism Description The missense mutation p.T315I (c.944C>T) in gene ABL1 cause the sensitivity of Axitinib by aberration of the drug's therapeutic target
Dasatinib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [2], [3], [4]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Sanger sequencing assay
Mechanism Description For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [5], [6]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Drug Resistance		 Flow cytometry assay; Analysis of disease free and overall survival assay
Mechanism Description Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4 (25886620). Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [2], [3], [7]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Sanger sequencing assay
Mechanism Description For CML patients on TkI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations. Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.
Imatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [8], [9]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.H396P
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 4WA9
Mutant Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2G2H
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.35
TM score: 0.96269
Amino acid change:
H396P
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
230
|
P
-
N
-
Y
-
D
-
K
-
W
-
E
-
M
-
E
-
R
-
240
|
T
-
D
-
I
-
T
-
M
-
K
G
H
H
K
M
L
S
G
P
250
|
G
N
G
Y
Q
D
Y
K
G
W
E
E
V
M
Y
E
E
R
G
T
260
|
V
D
W
I
K
T
K
M
Y
K
S
H
L
K
T
L
V
G
A
G
270
|
V
G
K
Q
T
Y
L
G
K
E
E
V
D
Y
T
E
M
G
E
V
280
|
V
W
E
K
E
K
F
Y
L
S
K
L
E
T
A
V
A
A
V
V
290
|
M
K
K
T
E
L
I
K
K
E
H
D
P
T
N
M
L
E
V
V
300
|
Q
E
L
E
L
F
G
L
V
K
C
E
T
A
R
A
E
V
P
M
310
|
P
K
F
E
Y
I
I
K
I
H
T
P
E
N
F
L
M
V
T
Q
320
|
Y
L
G
L
N
G
L
V
L
C
D
T
Y
R
L
E
R
P
E
P
330
|
C
F
N
Y
R
I
Q
I
E
T
V
E
N
F
A
M
V
T
V
Y
340
|
L
G
L
N
Y
L
M
L
A
D
T
Y
Q
L
I
R
S
E
S
C
350
|
A
N
M
R
E
Q
Y
E
L
V
E
N
K
A
K
V
N
V
F
L
360
|
I
L
H
Y
R
M
D
A
L
T
A
Q
A
I
R
S
N
S
C
A
370
|
L
M
V
E
G
Y
E
L
N
E
H
K
L
K
V
N
K
F
V
I
380
|
A
H
D
R
F
D
G
L
L
A
S
A
R
R
L
N
M
C
T
L
390
|
G
V
D
G
T
E
Y
N
T
H
A
L
H
V
A
K
G
V
A
A
400
|
K
D
F
F
P
G
I
L
K
S
W
R
T
L
A
M
P
T
E
G
410
|
S
D
L
T
A
Y
Y
T
N
A
K
P
F
A
S
G
I
A
K
K
420
|
S
F
D
P
V
I
W
K
A
W
F
T
G
A
V
P
L
E
L
S
430
|
W
L
E
A
I
Y
A
N
T
K
Y
F
G
S
M
I
S
K
P
S
440
|
Y
D
P
V
G
W
I
A
D
F
L
G
S
V
Q
L
V
L
Y
W
450
|
E
E
L
I
L
A
E
T
K
Y
D
G
Y
M
R
S
M
P
E
Y
460
|
R
P
P
G
E
I
G
D
C
L
P
S
E
Q
K
V
V
Y
Y
E
470
|
E
L
L
L
M
E
R
K
A
D
C
Y
W
R
Q
M
W
E
N
R
480
|
P
P
S
E
D
G
R
C
P
P
S
E
F
K
A
V
E
Y
I
E
490
|
H
L
Q
M
A
R
F
A
E
C
T
W
M
Q
F
W
Q
N
E
P
500
|
S
S
S
D
I
R
S
P
D
S
E
F
V
A
E
E
K
I
E
H
510
|
L
Q
G
A
K
F
-
E
-
T
-
M
-
F
-
Q
-
E
-
S
520
|
-
S
-
I
-
S
-
D
-
E
-
V
-
E
-
K
-
E
-
L
530
|
-
G
-
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
Bone marrow Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Pyrosequencing analysis
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [10], [11]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.H396P
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 4WA9
Mutant Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2G2H
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.35
TM score: 0.96269
Amino acid change:
H396P
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
-
S
-
230
|
P
-
N
-
Y
-
D
-
K
-
W
-
E
-
M
-
E
-
R
-
240
|
T
-
D
-
I
-
T
-
M
-
K
G
H
H
K
M
L
S
G
P
250
|
G
N
G
Y
Q
D
Y
K
G
W
E
E
V
M
Y
E
E
R
G
T
260
|
V
D
W
I
K
T
K
M
Y
K
S
H
L
K
T
L
V
G
A
G
270
|
V
G
K
Q
T
Y
L
G
K
E
E
V
D
Y
T
E
M
G
E
V
280
|
V
W
E
K
E
K
F
Y
L
S
K
L
E
T
A
V
A
A
V
V
290
|
M
K
K
T
E
L
I
K
K
E
H
D
P
T
N
M
L
E
V
V
300
|
Q
E
L
E
L
F
G
L
V
K
C
E
T
A
R
A
E
V
P
M
310
|
P
K
F
E
Y
I
I
K
I
H
T
P
E
N
F
L
M
V
T
Q
320
|
Y
L
G
L
N
G
L
V
L
C
D
T
Y
R
L
E
R
P
E
P
330
|
C
F
N
Y
R
I
Q
I
E
T
V
E
N
F
A
M
V
T
V
Y
340
|
L
G
L
N
Y
L
M
L
A
D
T
Y
Q
L
I
R
S
E
S
C
350
|
A
N
M
R
E
Q
Y
E
L
V
E
N
K
A
K
V
N
V
F
L
360
|
I
L
H
Y
R
M
D
A
L
T
A
Q
A
I
R
S
N
S
C
A
370
|
L
M
V
E
G
Y
E
L
N
E
H
K
L
K
V
N
K
F
V
I
380
|
A
H
D
R
F
D
G
L
L
A
S
A
R
R
L
N
M
C
T
L
390
|
G
V
D
G
T
E
Y
N
T
H
A
L
H
V
A
K
G
V
A
A
400
|
K
D
F
F
P
G
I
L
K
S
W
R
T
L
A
M
P
T
E
G
410
|
S
D
L
T
A
Y
Y
T
N
A
K
P
F
A
S
G
I
A
K
K
420
|
S
F
D
P
V
I
W
K
A
W
F
T
G
A
V
P
L
E
L
S
430
|
W
L
E
A
I
Y
A
N
T
K
Y
F
G
S
M
I
S
K
P
S
440
|
Y
D
P
V
G
W
I
A
D
F
L
G
S
V
Q
L
V
L
Y
W
450
|
E
E
L
I
L
A
E
T
K
Y
D
G
Y
M
R
S
M
P
E
Y
460
|
R
P
P
G
E
I
G
D
C
L
P
S
E
Q
K
V
V
Y
Y
E
470
|
E
L
L
L
M
E
R
K
A
D
C
Y
W
R
Q
M
W
E
N
R
480
|
P
P
S
E
D
G
R
C
P
P
S
E
F
K
A
V
E
Y
I
E
490
|
H
L
Q
M
A
R
F
A
E
C
T
W
M
Q
F
W
Q
N
E
P
500
|
S
S
S
D
I
R
S
P
D
S
E
F
V
A
E
E
K
I
E
H
510
|
L
Q
G
A
K
F
-
E
-
T
-
M
-
F
-
Q
-
E
-
S
520
|
-
S
-
I
-
S
-
D
-
E
-
V
-
E
-
K
-
E
-
L
530
|
-
G
-
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 CR-Abl sequencing assay
Experiment for
Drug Resistance		 Event-free survival assay
Mechanism Description M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [10]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Mechanism Description Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [12], [13], [14]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay; Allele-specific (AS)-RT-PCR assay
Mechanism Description We herein describe the development of a rapid allele-specific (AS)-RT-PCR assay to identify the T315I mutation, which confers full resistance to all available tyrosine-kinase inhibitors (TkI).
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [12], [13], [14]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Peripheral blood Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Mechanism Description Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [15]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 PCR-Invader assay; Direct sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.
Nilotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [16], [17]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Mechanism Description Our finding reflects the natural development of a T315I mutation within the hematopoietic system of the reported patient and indicates the importance of BCR-ABL1 mutation monitoring in more primitive cell populations. Considering the natural history of T315I development in this reported CML case, we hypothesize that BCR-ABL1 kD mutations may be pre-concentrated in more primitive CML cells, which subsequently expand into the PB.
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [4], [7], [16]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 RNA sequencing assay
Mechanism Description The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.
Ponatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [18]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Ponatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay
Mechanism Description Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Tyrosine kinase inhibitor
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [19]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Tyrosine kinase inhibitor
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [19]
Resistant Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Resistant Drug Tyrosine kinase inhibitor
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Mechanism Description There are several identified mechanisms of resistance to TkIs. The presence of ABL kinase domain point mutation, which could be detected by molecular methods is one of them. ABL mutation was detected in 19 (31,6%) patients. In four cases with detected mutation the disease has progressed to blast crisis.
References
Ref 1 Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformationNature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119. Epub 2015 Feb 9.
Ref 2 Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res. 2011 Jan;35(1):38-43. doi: 10.1016/j.leukres.2010.06.030. Epub 2010 Jul 29.
Ref 3 A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis. Int J Hematol. 2011 Feb;93(2):237-242. doi: 10.1007/s12185-011-0766-2. Epub 2011 Jan 25.
Ref 4 Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy. Haematologica. 2011 Jun;96(6):918-21. doi: 10.3324/haematol.2010.039321. Epub 2011 Feb 28.
Ref 5 Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. doi: 10.1182/blood-2011-05-351403. Epub 2011 Sep 19.
Ref 6 Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. doi: 10.1002/cncr.29646. Epub 2015 Aug 26.
Ref 7 Complexity of BCR-ABL kinase domain mutations during the course of therapy with tyrosine kinase inhibitors in chronic myeloid leukemia. Am J Hematol. 2009 Apr;84(4):256-7. doi: 10.1002/ajh.21366.
Ref 8 Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood. 2009 Sep 24;114(13):2598-605. doi: 10.1182/blood-2008-08-173674. Epub 2009 Jul 22.
Ref 9 Increased genomic instability may contribute to the development of kinase domain mutations in chronic myeloid leukemia. Int J Hematol. 2014 Dec;100(6):567-74. doi: 10.1007/s12185-014-1685-9. Epub 2014 Oct 4.
Ref 10 BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002 Feb 9;359(9305):487-91. doi: 10.1016/S0140-6736(02)07679-1.
Ref 11 Imatinib resistant BCR-ABL1 mutations at relapse in children with Ph+ ALL: a Children's Oncology Group (COG) study. Br J Haematol. 2012 May;157(4):507-10. doi: 10.1111/j.1365-2141.2012.09039.x. Epub 2012 Feb 2.
Ref 12 High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002 May 1;99(9):3472-5. doi: 10.1182/blood.v99.9.3472.
Ref 13 Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002 Aug;2(2):117-25. doi: 10.1016/s1535-6108(02)00096-x.
Ref 14 Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002 Nov;16(11):2190-6. doi: 10.1038/sj.leu.2402741.
Ref 15 BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay. Leuk Res. 2011 May;35(5):598-603. doi: 10.1016/j.leukres.2010.12.006. Epub 2011 Jan 15.
Ref 16 Use of direct sequencing for detection of mutations in the BCR-ABL kinase domain in Slovak patients with chronic myeloid leukemia. Neoplasma. 2011;58(6):548-53. doi: 10.4149/neo_2011_06_548.
Ref 17 Analysis of mutations in the BCR-ABL1 kinase domain, using direct sequencing: detection of the T315I mutation in bone marrow CD34+ cells of a patient with chronic myelogenous leukemia 6 months prior to its emergence in peripheral blood. Mol Diagn Ther. 2012 Jun 1;16(3):163-6. doi: 10.2165/11632420-000000000-00000.
Ref 18 Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127.
Ref 19 [ABL domain kinase point mutations as a cause of resistance to therapy of patients with chronic myeloid leukemia with tyrosine kinase inhibitors. Single center experience]. Przegl Lek. 2011;68(5):253-7.

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