Nuclear entrapment of BCR–ABL by combining imatinib mesylate with leptomycin B does not eliminate CD34+ chronic myeloid leukaemia cells

Chronic myeloid leukaemia (CML) arises from the formation of the Philadelphia (Ph+) chromosome in haematopoietic stem cells. The translated fusion oncoprotein, BCR–ABL (p210BCR−ABL), is a constitutively active tyrosine kinase (TK), which activates multiple proliferative and anti-apoptotic signalling pathways, causing deregulated cell growth.1 Despite impressive rates of complete cytogenetic response (CCyR) in the majority of patients treated with the targeted TK inhibitor (TKI), imatinib mesylate (IM; Glivec, Novartis, Basle, Switzerland),2 few patients achieve sustained molecular remission and a significant proportion develops resistance to IM.3 The presence of pre-existing or acquired BCR–ABL kinase domain mutations, which decrease IM binding,3 and the innate insensitivity of primitive quiescent CML stem cells to IM4 are two contributing resistance mechanisms. Consequently, many strategies have been investigated to overcome IM resistance, including the development of second-generation TKIs, nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol–Myers Squibb, Princeton, NJ, USA), although these remain ineffective against the T315I mutation.