Niemann-Pick disease type C1(NPC1) is involved in resistance against imatinib in the imatinib-resistant Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI

• An imatinib resistant and bcr-abl unmutated cell line SUP-B15/RI was established.
• Microarray showed that genes expressed differently between the two cell lines.
• NPC1 was higher expressed and the function was defect in SUP-B15/RI.
• The status of NPC1 in SUP-B15/RI lead to lower intracellular concentration of IM.

Niemann-Pick disease type C1 (NPC1) is involved in cholesterol trafficking and may normally function as a transmembrane efflux pump. Previous studies showed that its dysfunction can lead to cholesterol and daunorubicin accumulation in the cytoplasmic endosomal/lysosomal system, lead to Niemann-Pick disease and resistance to anticancer drugs. In the present study, NPC1 was shown by microarray analysis to be more highly expressed in the Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI, an imatinib-resistant variant of SUP-B15/S cells without bcr-abl gene mutation established in our lab. Further investigation revealed a defect in the functional capacity of the NPC1 protein demonstrated by filipin staining accompanied by a lower intracellular imatinib mesylate(IM) concentration by high-performance liquid chromatography in SUP-B15/RI compared with SUP-B15/S cells. Furthermore, U18666A, an inhibitor of NPC1 function, was used to block cholesterol trafficking to imitate the NPC1 defect in SUP-B15/S cells, leading to higher NPC1 expression, stronger filipin fluorescence, lower intracellular IM concentrations and greater resistance against IM. Samples from non-mutated relapsed Ph+ ALL patients also showed higher NPC1 expression compared with IM-sensitive patients. Our experiment may reveal a new mechanism of IM resistance in Ph+ ALL.