Table 1.

Point-mutations in the BCR-ABL kinase domain associated with imatinib resistance in chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) patients.

Nucleotide Change*Amino Acid Change†Proposed Mechanism of ResistanceNo. of Cases (Detected/Tested)‡Refs.
* Positions according to GenBank no. M14752. 
† Positions according to GenBank no. AAB60394 for ABL type 1a, and in brackets the corresponding position for Abl type 1b (where the N-terminal domain is 19-amino acids longer). 
‡ Among patients who developed resistance or never responded to imatinib. The table collates data from 8 independent series where patients were screened for DNA mutations in the tyrosine kinase region of Bcr-Abl. A total of 149 mutational events were reported in these 206 patients (with a few cases exhibiting more than 1 mutation in the resistant clone). This indicates that point mutations in the kinase domain account for approximately 72% of the cases where lack or loss of response to imatinib is observed in the clinic. No mutations were yet detected in primary or acquired resistance of patients in early chronic phase. 
A1094G M244V (M263V) Impairs conformational change (?) 1/32 14  
   1/66 16  
   1/27 75  
C1106G L248V (L267V) Impairs conformational change 1/27 75  
G1113A G250E (G269E) Impairs conformational change 2/28 15  
   2/32 14  
   2/27 75  
A1119G Q252R (Q271R) Impairs conformational change 1/32 14  
G1120C/T Q252H (Q271H) Impairs conformational change 6/32 14  
   1/66 16  
   5/27 75  
T1121C Y253H (Y272H) Impairs conformational change 2/8 72  
   1/28 15  
   2/32 14  
   4/66 16  
A1122T Y253F (Y272F) Impairs conformational change 3/32 14  
   1/66 16  
   2/27 75  
G1127A E255K (E274K) Impairs conformational change 1/12 97  
   2/8 72  
   4/28 15  
   6/9 142 
   10/32 14  
   3/66 16  
   2/27 75  
A1128T E255V (E274V) Impairs conformational change 1/8 72  
   1/66 16  
   1/27 75  
T1495C F311L (F330L) Unknown 1/24 73  
C1308T T315I (T334I) Affects imatinib binding 2/8 72  
   10/32 14  
   3/28 15  
   1/9 141  
   3/24 73  
   6/66 16  
   2/27 75  
C1315G F317L (F336L) Affects imatinib binding 1/28 15  
   3/32 14  
T1392C M343T (M362T) Unknown 1/32 14  
T1416C M351T (M370T) Impairs conformational change 2/28 15  
   10/32 14  
   1/24 73  
   4/66 16  
   7/27 75  
A1428G E355G (E374G) Impairs conformational change 1/32 14  
   1/66 16  
   2/27 75  
T1439G F359V F378V) Affects imatinib binding (?) 2/32 14  
   2/27 75  
G1499A V379I (V398I) Impairs conformational change (?) 1/32 14  
T1508C F382L (F401L) Unknown 1/32 14  
T1523A L387M (L406M) Impairs conformational change (?) 1/32 14  
A1551G H396R (H415R) Impairs conformational change (?) 3/32 14  
   1/66 16  
   1/27 75  
C1614A S417Y (S436Y) Unknown 1/27 75  
G1739A E459K (E478K) Unknown 1/27 75  
T1821C F486S (F505S) Unknown 1/27 75  
Nucleotide Change*Amino Acid Change†Proposed Mechanism of ResistanceNo. of Cases (Detected/Tested)‡Refs.
* Positions according to GenBank no. M14752. 
† Positions according to GenBank no. AAB60394 for ABL type 1a, and in brackets the corresponding position for Abl type 1b (where the N-terminal domain is 19-amino acids longer). 
‡ Among patients who developed resistance or never responded to imatinib. The table collates data from 8 independent series where patients were screened for DNA mutations in the tyrosine kinase region of Bcr-Abl. A total of 149 mutational events were reported in these 206 patients (with a few cases exhibiting more than 1 mutation in the resistant clone). This indicates that point mutations in the kinase domain account for approximately 72% of the cases where lack or loss of response to imatinib is observed in the clinic. No mutations were yet detected in primary or acquired resistance of patients in early chronic phase. 
A1094G M244V (M263V) Impairs conformational change (?) 1/32 14  
   1/66 16  
   1/27 75  
C1106G L248V (L267V) Impairs conformational change 1/27 75  
G1113A G250E (G269E) Impairs conformational change 2/28 15  
   2/32 14  
   2/27 75  
A1119G Q252R (Q271R) Impairs conformational change 1/32 14  
G1120C/T Q252H (Q271H) Impairs conformational change 6/32 14  
   1/66 16  
   5/27 75  
T1121C Y253H (Y272H) Impairs conformational change 2/8 72  
   1/28 15  
   2/32 14  
   4/66 16  
A1122T Y253F (Y272F) Impairs conformational change 3/32 14  
   1/66 16  
   2/27 75  
G1127A E255K (E274K) Impairs conformational change 1/12 97  
   2/8 72  
   4/28 15  
   6/9 142 
   10/32 14  
   3/66 16  
   2/27 75  
A1128T E255V (E274V) Impairs conformational change 1/8 72  
   1/66 16  
   1/27 75  
T1495C F311L (F330L) Unknown 1/24 73  
C1308T T315I (T334I) Affects imatinib binding 2/8 72  
   10/32 14  
   3/28 15  
   1/9 141  
   3/24 73  
   6/66 16  
   2/27 75  
C1315G F317L (F336L) Affects imatinib binding 1/28 15  
   3/32 14  
T1392C M343T (M362T) Unknown 1/32 14  
T1416C M351T (M370T) Impairs conformational change 2/28 15  
   10/32 14  
   1/24 73  
   4/66 16  
   7/27 75  
A1428G E355G (E374G) Impairs conformational change 1/32 14  
   1/66 16  
   2/27 75  
T1439G F359V F378V) Affects imatinib binding (?) 2/32 14  
   2/27 75  
G1499A V379I (V398I) Impairs conformational change (?) 1/32 14  
T1508C F382L (F401L) Unknown 1/32 14  
T1523A L387M (L406M) Impairs conformational change (?) 1/32 14  
A1551G H396R (H415R) Impairs conformational change (?) 3/32 14  
   1/66 16  
   1/27 75  
C1614A S417Y (S436Y) Unknown 1/27 75  
G1739A E459K (E478K) Unknown 1/27 75  
T1821C F486S (F505S) Unknown 1/27 75  
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