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.

The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.

IACOBUCCI, ILARIA;MARTINELLI, GIOVANNI;
2009

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.
Klemm L; Duy C; Iacobucci I; Kuchen S; von Levetzow G; Feldhahn N; Henke N; Li Z; Hoffmann TK; Kim YM; Hofmann WK; Jumaa H; Groffen J; Heisterkamp N; Martinelli G; Lieber MR; Casellas R; Müschen M.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/82906
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