TY - JOUR
T1 - The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia
AU - Klemm, Lars
AU - Duy, Cihangir
AU - Iacobucci, Ilaria
AU - Kuchen, Stefan
AU - von Levetzow, Gregor
AU - Feldhahn, Niklas
AU - Henke, Nadine
AU - Li, Zhiyu
AU - Hoffmann, Thomas K.
AU - Kim, Yong mi
AU - Hofmann, Wolf Karsten
AU - Jumaa, Hassan
AU - Groffen, John
AU - Heisterkamp, Nora
AU - Martinelli, Giovanni
AU - Lieber, Michael R.
AU - Casellas, Rafael
AU - Müschen, Markus
PY - 2009/9/8
Y1 - 2009/9/8
N2 - 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.
AB - 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=69249236962&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2009.07.030
DO - 10.1016/j.ccr.2009.07.030
M3 - Article
C2 - 19732723
SN - 1535-6108
VL - 16
SP - 232
EP - 245
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -