Disease Information

General Information of the Disease (ID: DIS00055)
Name
Chronic lymphocytic leukemia
ICD
ICD-11: 2A82
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  MRAP: Metabolic Reprogramming via Altered Pathways
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Bendamustine hydrochloride
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cellular tumor antigen p53 (TP53) [3]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Bendamustine hydrochloride
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole exome sequencing assay; Targeted deep sequencing assay; Sanger sequencing assay
Mechanism Description Following exposure to chemoimmunotherapy, the resistant TP53 aberrant clones accumulate and dominate the tumour.
Fludarabine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: 17p13 (Unclear) [4]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Structural variation
Copy number loss
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 FISH assay
Experiment for
Drug Resistance		 Multivariable Andersen-Gill regression analysis; VH sequencing assay
Mechanism Description Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-181a [5]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.
Key Molecule: hsa-mir-221 [5]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Protocadherin Fat 1 (FAT1) [6]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation JAKT/STAT signaling pathway Activation hsa04630
Wnt signaling pathway Activation hsa04310
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 White blood cell count assay
Mechanism Description FAT1 and its mutational inactivation have been linked to activation of the WNT pathway in solid tumors and to chemoresistance in chronic lymphocytic leukemia and could serve as an attractive therapeutic target.
Key Molecule: Cellular tumor antigen p53 (TP53) [7]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation NF-kB signaling pathway Inhibition hsa04218
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.
Key Molecule: Serine-protein kinase ATM (ATM) [7]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation NF-kB signaling pathway Inhibition hsa04218
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-181a [8]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model CLL B cells Lymph Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.
Key Molecule: hsa-mir-181 [8]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model CLL B cells Lymph Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [8]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model CLL B cells Lymph Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [8]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model CLL B cells Lymph Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.
Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [8]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model CLL B cells Lymph Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.
Ibrutinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase BTK (BTK) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.C481S
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VXQ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.33  Å
PDB: 8FLN
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.82
TM score: 0.96927
Amino acid change:
C481S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
P
-
L
-
370
|
G
-
S
-
R
-
L
-
K
-
Y
-
P
-
V
-
S
-
Q
-
380
|
Q
-
N
-
K
-
N
-
A
-
P
-
S
-
T
G
A
M
G
G
390
|
L
L
G
G
Y
Y
G
G
S
S
W
W
E
E
I
I
D
D
P
P
400
|
K
K
D
D
L
L
T
T
F
F
L
L
K
K
E
E
L
L
G
G
410
|
T
T
G
G
Q
Q
F
F
G
G
V
V
V
V
K
K
Y
Y
G
G
420
|
K
K
W
W
R
R
G
G
Q
Q
Y
Y
D
D
V
V
A
A
I
I
430
|
K
K
M
M
I
I
K
K
E
E
G
G
S
S
M
M
S
S
E
E
440
|
D
D
E
E
F
F
I
I
E
E
E
E
A
A
K
K
V
V
M
M
450
|
M
M
N
N
L
L
S
S
H
H
E
E
K
K
L
L
V
V
Q
Q
460
|
L
L
Y
Y
G
G
V
V
C
C
T
T
K
K
Q
Q
R
R
P
P
470
|
I
I
F
F
I
I
I
I
T
T
E
E
Y
Y
M
M
A
A
N
N
480
|
G
G
C
S
L
L
L
L
N
N
Y
Y
L
L
R
R
E
E
M
M
490
|
R
R
H
H
R
R
F
F
Q
Q
T
T
Q
Q
Q
Q
L
L
L
L
500
|
E
E
M
M
C
C
K
K
D
D
V
V
C
C
E
E
A
A
M
M
510
|
E
E
Y
Y
L
L
E
E
S
S
K
K
Q
Q
F
F
L
L
H
H
520
|
R
R
D
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
530
|
N
N
D
D
Q
Q
G
G
V
V
V
V
K
K
V
V
S
S
D
D
540
|
F
F
G
G
L
L
S
S
R
R
Y
Y
V
V
L
L
D
D
D
D
550
|
E
E
Y
Y
T
T
S
S
S
S
V
V
G
G
S
S
K
K
F
F
560
|
P
P
V
V
R
R
W
W
S
S
P
P
P
P
E
E
V
V
L
L
570
|
M
M
Y
Y
S
S
K
K
F
F
S
S
S
S
K
K
S
S
D
D
580
|
I
I
W
W
A
A
F
F
G
G
V
V
L
L
M
M
W
W
E
E
590
|
I
I
Y
Y
S
S
L
L
G
G
K
K
M
M
P
P
Y
Y
E
E
600
|
R
R
F
F
T
T
N
N
S
S
E
E
T
T
A
A
E
E
H
H
610
|
I
I
A
A
Q
Q
G
G
L
L
R
R
L
L
Y
Y
R
R
P
P
620
|
H
H
L
L
A
A
S
S
E
E
K
K
V
V
Y
Y
T
T
I
I
630
|
M
M
Y
Y
S
S
C
C
W
W
H
H
E
E
K
K
A
A
D
D
640
|
E
E
R
R
P
P
T
T
F
F
K
K
I
I
L
L
L
L
S
S
650
|
N
N
I
I
L
L
D
D
V
V
M
M
D
D
E
E
E
E
S
S
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: Tyrosine-protein kinase BTK (BTK) [10]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.C481S
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VXQ
Mutant Type Structure Method: X-ray diffraction Resolution: 1.33  Å
PDB: 8FLN
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.82
TM score: 0.96927
Amino acid change:
C481S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
P
-
L
-
370
|
G
-
S
-
R
-
L
-
K
-
Y
-
P
-
V
-
S
-
Q
-
380
|
Q
-
N
-
K
-
N
-
A
-
P
-
S
-
T
G
A
M
G
G
390
|
L
L
G
G
Y
Y
G
G
S
S
W
W
E
E
I
I
D
D
P
P
400
|
K
K
D
D
L
L
T
T
F
F
L
L
K
K
E
E
L
L
G
G
410
|
T
T
G
G
Q
Q
F
F
G
G
V
V
V
V
K
K
Y
Y
G
G
420
|
K
K
W
W
R
R
G
G
Q
Q
Y
Y
D
D
V
V
A
A
I
I
430
|
K
K
M
M
I
I
K
K
E
E
G
G
S
S
M
M
S
S
E
E
440
|
D
D
E
E
F
F
I
I
E
E
E
E
A
A
K
K
V
V
M
M
450
|
M
M
N
N
L
L
S
S
H
H
E
E
K
K
L
L
V
V
Q
Q
460
|
L
L
Y
Y
G
G
V
V
C
C
T
T
K
K
Q
Q
R
R
P
P
470
|
I
I
F
F
I
I
I
I
T
T
E
E
Y
Y
M
M
A
A
N
N
480
|
G
G
C
S
L
L
L
L
N
N
Y
Y
L
L
R
R
E
E
M
M
490
|
R
R
H
H
R
R
F
F
Q
Q
T
T
Q
Q
Q
Q
L
L
L
L
500
|
E
E
M
M
C
C
K
K
D
D
V
V
C
C
E
E
A
A
M
M
510
|
E
E
Y
Y
L
L
E
E
S
S
K
K
Q
Q
F
F
L
L
H
H
520
|
R
R
D
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
530
|
N
N
D
D
Q
Q
G
G
V
V
V
V
K
K
V
V
S
S
D
D
540
|
F
F
G
G
L
L
S
S
R
R
Y
Y
V
V
L
L
D
D
D
D
550
|
E
E
Y
Y
T
T
S
S
S
S
V
V
G
G
S
S
K
K
F
F
560
|
P
P
V
V
R
R
W
W
S
S
P
P
P
P
E
E
V
V
L
L
570
|
M
M
Y
Y
S
S
K
K
F
F
S
S
S
S
K
K
S
S
D
D
580
|
I
I
W
W
A
A
F
F
G
G
V
V
L
L
M
M
W
W
E
E
590
|
I
I
Y
Y
S
S
L
L
G
G
K
K
M
M
P
P
Y
Y
E
E
600
|
R
R
F
F
T
T
N
N
S
S
E
E
T
T
A
A
E
E
H
H
610
|
I
I
A
A
Q
Q
G
G
L
L
R
R
L
L
Y
Y
R
R
P
P
620
|
H
H
L
L
A
A
S
S
E
E
K
K
V
V
Y
Y
T
T
I
I
630
|
M
M
Y
Y
S
S
C
C
W
W
H
H
E
E
K
K
A
A
D
D
640
|
E
E
R
R
P
P
T
T
F
F
K
K
I
I
L
L
L
L
S
S
650
|
N
N
I
I
L
L
D
D
V
V
M
M
D
D
E
E
E
E
S
S
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Mechanism Description Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.
Key Molecule: Tyrosine-protein kinase BTK (BTK) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.C481R
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: AKT serine/threonine kinase (AKT) [11]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model CD5+19+ cells Blood Homo sapiens (Human) N.A.
MEC1 cells Blood Homo sapiens (Human) CVCL_1870
HS-5 cells Bone marrow Homo sapiens (Human) CVCL_3720
In Vivo Model NSG mice model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Induction of transcription factor FoxO1 during ibrutinib therapy upregulates Rictor, an mTORC2 assembly protein, leading to phosphorylation of Akt, an essential molecule supporting CLL cell survival
Key Molecule: Forkhead box protein O1/Rapamycin-insensitive companion of mTOR (FOXO1/RICTOR) axis [11]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Expression
p.Y537N
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model CD5+19+ cells Blood Homo sapiens (Human) N.A.
MEC1 cells Blood Homo sapiens (Human) CVCL_1870
HS-5 cells Bone marrow Homo sapiens (Human) CVCL_3720
In Vivo Model NSG mice model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Induction of transcription factor FoxO1 during ibrutinib therapy upregulates Rictor, an mTORC2 assembly protein, leading to phosphorylation of Akt, an essential molecule supporting CLL cell survival
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.S707Y
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.P664W
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.P664S
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [9]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.L845F
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Key Molecule: Phosphoinositide phospholipase C-gamma-2 (PLCG2) [10]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Mutation
p.R665W+p.L845F+p.S707Y
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Mechanism Description In contrast to the BTKC481S mutation, which causes eventual loss of BTK inhibition by ibrutinib, PLCG2 mutations are all potentially gain-of-function mutations. Situated downstream from BTK, PLCG2 mutations allow for continued signalling regardless of BTK activity. After stimulation with anti-IgM antibody, cells with either the PLCG2R665W or PLCG2L845F mutations were found to have sustained BCR signalling that was not inhibited by ibrutinib, as measured by calcium-flux assays and phosphorylation of ERK and AKT.
Key Molecule: Tyrosine-protein kinase BTK (BTK) [2]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Rho GTPases signaling pathway Regulation N.A.
MAPK signaling pathway Activation hsa04010
WNT/beta-catenin signaling pathway Regulation N.A.
NOTCH signaling pathway Activation hsa04330
In Vitro Model HG-3 CLL cells Blood Homo sapiens (Human) N.A.
OSU-CLL cells Blood Homo sapiens (Human) CVCL_Y382
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 RNA sequencing assay; ROS assay; Ferroptosis assay; Flow cytometry assay
Mechanism Description Clinically, most ibrutinib-resistant patients (~80%) harbor a C481S mutation in the BTK protein, blocking ibrutinib from covalently binding to BTK, and/or a gain of function mutation in PLCgamma2, activating downstream BCR signaling independent of BTK inhibition. Resistance is also mediated through alternative survival pathways, such as the activation of PI3K/AKT/ERK signaling .
Rituximab
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: 17p13 (Unclear) [4]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Rituximab
 Drug Info 
Molecule Alteration Structural variation
Copy number loss
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 FISH assay
Experiment for
Drug Resistance		 Multivariable Andersen-Gill regression analysis; VH sequencing assay
Mechanism Description Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [12]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Rituximab
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Notch signaling pathway Activation hsa04330
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Mutations in NOTCH1 result in increased stability of an activated intracellular NOTCH1 isoform, which confers cell survival and apoptosis resistance, in part by sustaining expression of the anti-apoptotic protein Mcl-1, and promoting the activity of the key translational regulator eIF4E. Compared with wild-type cases, NOTCH1-mutated cases have progressive disease and significantly shorter survival, and demonstrate resistance to the anti-CD20 monoclo.l antibody rituximab, a phenotype thought to be associated with the low CD20 levels and dysregulation of histone deacetylases(HDAC)-mediated epigenetic repression of CD20 expression observed in NOTCH1-mutated CLL.
Key Molecule: Cellular tumor antigen p53 (TP53) [3]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Rituximab
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole exome sequencing assay; Targeted deep sequencing assay; Sanger sequencing assay
Mechanism Description Following exposure to chemoimmunotherapy, the resistant TP53 aberrant clones accumulate and dominate the tumour.
Venetoclax
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [13]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Venetoclax
 Drug Info 
Molecule Alteration Missense mutation
p.G101V (c.302G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model KMS-12-PE cells Pleural effusion Homo sapiens (Human) CVCL_1333
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Bcl-2-binding component 3 (BBC3) [14]
Metabolic Type Mitochondrial metabolism
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Venetoclax
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model B-cell lymphoma cells Blood Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) [2]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Venetoclax
 Drug Info 
Molecule Alteration Function
Activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TNF signaling pathway Activation hsa04668
Toll-like receptor signaling pathway Activation hsa04620
NF-kB signaling pathway Activation hsa04218
RANK-L/RANK signaling pathway Regulation N.A.
In Vitro Model HG-3 CLL cells Blood Homo sapiens (Human) N.A.
OSU-CLL cells Blood Homo sapiens (Human) CVCL_Y382
Experiment for
Molecule Alteration		 Pathway enrichment analysis
Experiment for
Drug Resistance		 RNA sequencing assay; ROS assay; Ferroptosis assay; Flow cytometry assay
Mechanism Description Venetoclax resistance can be driven by the upregulation of other anti-apoptotic BCL2 family members such as BCL-xL and MCL1 by NF-kappaB activation.
Investigative Drug(s)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
10,12-Tricosadiynoic Acid
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Acyl-CoA oxidase 1 (ACOX1) [15]
Metabolic Type Lipid metabolism
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug 10,12-Tricosadiynoic Acid
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HG3 cells Blood Homo sapiens (Human) CVCL_Y547
MEC1 cells Blood Homo sapiens (Human) CVCL_1870
OSU-CLL cells Blood Homo sapiens (Human) CVCL_Y382
PGA1 cells Blood Homo sapiens (Human) CVCL_Y545
Primary B-lymphocytes cells Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 qPCR, immunoblot and confocal microscopy approaches
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Accordingly, downmodulation of ACOX1 (a rate-limiting pFAO enzyme overexpressed in CLL cells) was enough to shift the CLL cells' metabolism from lipids to a carbon- and amino-acid-based phenotype. Complete blockade of ACOX1 resulted in lipid droplet accumulation and caspase-dependent death in CLL cells, including those from individuals with poor cytogenetic and clinical prognostic factors.
Inhibitory peptide L-JNKi
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mitogen-activated protein kinase 8 (MAPK8) [1]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug Inhibitory peptide L-JNKi
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation B cell receptor signaling pathway Inhibition hsa04662
In Vitro Model 3T3-msCD40L cells Embryo Homo sapiens (Human) CVCL_1H10
M2-10B4 cells Bone marrow Homo sapiens (Human) CVCL_5794
In Vivo Model NOG mice; Eu-TCL1-tg mice Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
Purine analogues
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cellular tumor antigen p53 (TP53) [16]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Resistant Drug Purine analogues
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 karyotyping assay
Mechanism Description TP53 abnormalities lead to resistance to purine a.logues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL).
Preclinical Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
JNK1 inhibitors
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug JNK1 inhibitors
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation B cell receptor signaling pathway Inhibition hsa04662
In Vitro Model 3T3-msCD40L cells Embryo Homo sapiens (Human) CVCL_1H10
M2-10B4 cells Bone marrow Homo sapiens (Human) CVCL_5794
In Vivo Model NOG mice; Eu-TCL1-tg mice Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
Key Molecule: Mitogen-activated protein kinase 8 (MAPK8) [1]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug JNK1 inhibitors
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation B cell receptor signaling pathway Inhibition hsa04662
In Vitro Model 3T3-msCD40L cells Embryo Homo sapiens (Human) CVCL_1H10
M2-10B4 cells Bone marrow Homo sapiens (Human) CVCL_5794
In Vivo Model NOG mice; Eu-TCL1-tg mice Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
Key Molecule: B-cell lymphoma 2 (BCL2) [1]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug JNK1 inhibitors
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation B cell receptor signaling pathway Inhibition hsa04662
In Vitro Model 3T3-msCD40L cells Embryo Homo sapiens (Human) CVCL_1H10
M2-10B4 cells Bone marrow Homo sapiens (Human) CVCL_5794
In Vivo Model NOG mice; Eu-TCL1-tg mice Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
Key Molecule: Oncogenic transcription factor c-Jun [1]
Sensitive Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
Sensitive Drug JNK1 inhibitors
 Drug Info 
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation B cell receptor signaling pathway Inhibition hsa04662
In Vitro Model 3T3-msCD40L cells Embryo Homo sapiens (Human) CVCL_1H10
M2-10B4 cells Bone marrow Homo sapiens (Human) CVCL_5794
In Vivo Model NOG mice; Eu-TCL1-tg mice Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
References
Ref 1 JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. J Exp Med. 2025 Jan 6;222(1):e20230681.
Ref 2 The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato. 2024 Sep;5(3):321-339.
Ref 3 Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease. Leukemia. 2016 Jun;30(6):1301-10. doi: 10.1038/leu.2016.10. Epub 2016 Feb 5.
Ref 4 Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007 Sep;92(9):1242-5. doi: 10.3324/haematol.10720. Epub 2007 Aug 1.
Ref 5 Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia. Mol Cancer. 2010 May 20;9:115. doi: 10.1186/1476-4598-9-115.
Ref 6 Mutational spectrum of adult T-ALL. Oncotarget. 2015 Feb 20;6(5):2754-66. doi: 10.18632/oncotarget.2218.
Ref 7 FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.
Ref 8 miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Carcinogenesis. 2012 Jul;33(7):1294-301. doi: 10.1093/carcin/bgs179. Epub 2012 May 18.
Ref 9 Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
Ref 10 Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427
Ref 11 FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia. J Clin Invest. 2024 Oct 22;134(23):e173770.
Ref 12 The mutational signature of chronic lymphocytic leukemia. Biochem J. 2016 Nov 1;473(21):3725-3740. doi: 10.1042/BCJ20160256.
Ref 13 Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutationsNat Commun. 2019 Jun 3;10(1):2385. doi: 10.1038/s41467-019-10363-1.
Ref 14 Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood. 2022 Nov 17;140(20):2113-2126.
Ref 15 ACOX1-mediated peroxisomal fatty acid oxidation contributes to metabolic reprogramming and survival in chronic lymphocytic leukemia. Leukemia. 2024 Feb;38(2):302-317.
Ref 16 TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes. Int J Cancer. 2016 Oct 15;139(8):1759-63. doi: 10.1002/ijc.30222. Epub 2016 Jun 24.

If you find any error in data or bug in web service, please kindly report it to Dr. Sun and Dr. Yu.