The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.
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.
Klemm
Lars
L
Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
Duy
Cihangir
C
Iacobucci
Ilaria
I
Kuchen
Stefan
S
von Levetzow
Gregor
G
Feldhahn
Niklas
N
Henke
Nadine
N
Li
Zhiyu
Z
Hoffmann
Thomas K
TK
Kim
Yong-mi
YM
Hofmann
Wolf-Karsten
WK
Jumaa
Hassan
H
Groffen
John
J
Heisterkamp
Nora
N
Martinelli
Giovanni
G
Lieber
Michael R
MR
Casellas
Rafael
R
Müschen
Markus
M
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049410:Luciferases, Renilla / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D049452:Green Fluorescent Proteins; D000068877:Imatinib Mesylate; D049410:Luciferases, Renilla; D016044:Fusion Proteins, bcr-abl; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase