Combination of chloroquine treatment has possibility of overcome T315I mutated Ph+ALL cells: establishment of two cell lines of double Ph+ALL with or without T315I mutation from one clinical course

Resistance to imatinib is still problematic in Ph-positive acute lymphoblastic leukemia (Ph+ALL). In this study, we established a Ph+ALL cell line, DPAL, which had the wild-type version of BCR/ABL, and a T315I mutant Ph+ALL cell line, DPAL/T315I, from one clinical course. At diagnosis, this patient had double Philadelphia chromosomes with some additional chromosomal abnormalities, but no point mutation in BCR/ABL. After combination treatment of imatinib with chemotherapy, the T315I mutation appeared, and the DPAL/T315I cell line also had double Philadelphia chromosomes without additional chromosomal abnormalities. This result suggested that some heterogeneous populations of BCR/ABL mutants exist in Ph+ALL at diagnosis. Imatinib combined treatment might be only select the dominancy of mutant gene. Our established cell line, DPAL/T315I had severe resistance to imatinib and 2nd tyrosine kinase, dasatinib, though, chloroquine combined treatment with imatinib or the HDAC inhibitor, SAHA induced cell death in DPAL/T315I cells in vitro. The utilize of chloroquine may prove to be a new strategy for eliminating imatinib-resistant Ph+ALL cells, especially T315I mutant positive cells.