The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia

被引：123

作者：

Klemm, Lars ^{[1
,2
,3
]}

Duy, Cihangir ^{[1
,2
,3
]}

Iacobucci, Ilaria ^{[4
]}

Kuchen, Stefan ^{[5
]}

von Levetzow, Gregor ^{[1
,2
,3
]}

Feldhahn, Niklas ^{[3
]}

Henke, Nadine ^{[3
]}

Li, Zhiyu ^{[5
]}

Hoffmann, Thomas K. ^{[3
,8
]}

Kim, Yong-mi ^{[1
,2
]}

Hofmann, Wolf-Karsten ^{[6
]}

Jumaa, Hassan ^{[7
]}

Groffen, John ^{[1
,2
]}

Heisterkamp, Nora ^{[1
,2
]}

Martinelli, Giovanni ^{[4
]}

Lieber, Michael R. ^{[1
]}

Casellas, Rafael ^{[5
]}

Mueschen, Markus ^{[1
,2
,3
]}

机构：

[1] Univ So Calif, Leukemia & Lymphoma Program, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90027 USA

[2] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA

[3] Univ Dusseldorf, D-40225 Dusseldorf, Germany

[4] Univ Bologna, Dept Hematol & Oncol L & A Seragnoli, I-40138 Bologna, Italy

[5] NIAMSD, NIH, Bethesda, MD 20892 USA

[6] Univ Heidelberg Hosp, Dept Hematol Oncol, D-68167 Mannheim, Germany

[7] Max Planck Inst Immunobiol, Freiburg, Germany

[8] Univ Duisburg Essen, Dept Otorhinolaryngol, D-45147 Essen, Germany

来源：

CANCER CELL | 2009年 / 16卷 / 03期

关键词：

INDUCED CYTIDINE DEAMINASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; KINASE DOMAIN MUTATIONS; ACTIVATION-INDUCED DEAMINASE; CLASS SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; TYROSINE KINASE; DNA DEAMINATION; CHRONIC PHASE; C-MYC;

D O I：

10.1016/j.ccr.2009.07.030

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Chronic myeloid leukemia (CIVIL) 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 CIVIL cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CIVIL 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.

引用

页码：232 / 245

页数：14

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