Abstract
Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
B-Lymphocytes / drug effects*
-
B-Lymphocytes / pathology
-
Benzamides
-
Blast Crisis / drug therapy*
-
Cell Line, Tumor
-
Cytidine Deaminase / metabolism*
-
Drug Resistance, Neoplasm / genetics*
-
Fusion Proteins, bcr-abl / genetics
-
Green Fluorescent Proteins / metabolism
-
Humans
-
Imatinib Mesylate
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Luciferases, Renilla / metabolism
-
Mice
-
Mice, Inbred BALB C
-
Mice, Knockout
-
Mice, SCID
-
Mice, Transgenic
-
Mutation*
-
Piperazines / therapeutic use*
-
Pyrimidines / therapeutic use*
-
Xenograft Model Antitumor Assays
Substances
-
Benzamides
-
Piperazines
-
Pyrimidines
-
Green Fluorescent Proteins
-
Imatinib Mesylate
-
Luciferases, Renilla
-
Fusion Proteins, bcr-abl
-
AICDA (activation-induced cytidine deaminase)
-
Cytidine Deaminase
Associated data
-
GEO/GSE13611
-
GEO/GSE13612
-
GEO/GSE15093