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

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• 作者：Lars Klemm ; Cihangir Duy ; Ilaria Iacobucci ; Stefan Kuchen ; Gregor von Levetzow ; Niklas Feldhahn ; Nadine Henke ; Zhiyu Li ; Thomas K. Hoffmann ; Yong-mi Kim ; Wolf-Karsten Hofmann ; Hassan Jumaa ; John Groffen ; Nora Heisterkamp ; Giovanni Martinelli ; Michael R. Lieber ; Rafael Casellas ; Markus Mü ; schen
• 刊名：Cancer Cell
• 出版年：2009
• 出版时间：8 September 2009
• 年：2009
• 卷：16
• 期：3
• 页码：232-245
• 全文大小：1607 K

文摘

Summary

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.