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Background  Resistance to chemotherapy is the most common cause of treatment failure in acute myeloid leukemia (AML) and the drug efflux pump ABCB1 is a critical mediator. Recent studies have identified promoter translocations as common drivers of high  ABCB1  expression in recurrent, chemotherapy-treated high-grade serous ovarian cancer (HGSC) and breast cancer. These fusions place  ABCB1  under the control of a strong promoter while leaving its open reading frame intact. The mechanisms controlling high  ABCB1  expression in AML are largely unknown. We therefore established an experimental system and analysis pipeline to determine whether promoter translocations account for high  ABCB1  expression in cases of relapsed human AML.    Methods  The human AML cell line THP-1 was used to create a model of chemotherapy resistance in which  ABCB1  expression was driven by a promoter fusion. The THP-1 model was used to establish a targeted nanopore long-read sequencing approach that was then applied to cases of  ABCB1  high  HGSC and AML. H3K27Ac ChIP sequencing was used to assess the activity of native promoters in cases of  ABCB1  high  AML.    Results  Prolonged in vitro daunorubicin exposure induced activating  ABCB1  promoter translocations in human THP-1 AML cells, similar to those recently described in recurrent high-grade serous ovarian and breast cancers. Targeted nanopore sequencing proved an efficient method for identifying  ABCB1  structural variants in THP-1 AML cells and HGSC; the promoter translocations identified in HGSC were both previously described and novel. In contrast, activating  ABCB1  promoter translocations were not identified in  ABCB1  high  AML; instead H3K27Ac ChIP sequencing demonstrated active native promoters in all cases studied.    Conclusions  Despite frequent high level expression of  ABCB1  in relapsed primary AML we found no evidence of  ABCB1  translocations and instead confirmed high-level activity of native  ABCB1  promoters, consistent with endogenous regulation.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12885-020-07571-0.

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in cancer