An unexpected protein interaction promotes drug resistance in leukemia

Aaron Pitre, Yubin Ge, Wenwei Lin, Yao Wang, Yu Fukuda, Jamshid Temirov, Aaron H. Phillips, Jennifer L. Peters, Yiping Fan, Jing Ma, Amanda Nourse, Chandrima Sinha, Hai Lin, Richard Kriwacki, James R. Downing, Tanja A. Gruber, Victoria E. Centonze, Anjaparavanda P. Naren, Taosheng Chen and John D. Schuetz ()
Additional contact information
Aaron Pitre: St. Jude Children’s Research Hospital (SJCRH)
Yubin Ge: Wayne State University School of Medicine
Wenwei Lin: St. Jude Children’s Research Hospital (SJCRH)
Yao Wang: St. Jude Children’s Research Hospital (SJCRH)
Yu Fukuda: St. Jude Children’s Research Hospital (SJCRH)
Jamshid Temirov: St. Jude Children’s Research Hospital (SJCRH)
Aaron H. Phillips: St. Jude Children’s Research Hospital (SJCRH)
Jennifer L. Peters: St. Jude Children’s Research Hospital (SJCRH)
Yiping Fan: St. Jude Children’s Research Hospital (SJCRH)
Jing Ma: St. Jude Children’s Research Hospital (SJCRH)
Amanda Nourse: St. Jude Children’s Research Hospital (SJCRH)
Chandrima Sinha: University of Tennessee Health Sciences Center
Hai Lin: The First Hospital of Jilin University
Richard Kriwacki: St. Jude Children’s Research Hospital (SJCRH)
James R. Downing: St. Jude Children’s Research Hospital (SJCRH)
Tanja A. Gruber: St. Jude Children’s Research Hospital (SJCRH)
Victoria E. Centonze: St. Jude Children’s Research Hospital (SJCRH)
Anjaparavanda P. Naren: Cincinnati Children’s Hospital Medical Center
Taosheng Chen: St. Jude Children’s Research Hospital (SJCRH)
John D. Schuetz: St. Jude Children’s Research Hospital (SJCRH)

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance. Specific disruption of this protein complex, either genetically or chemically, removed ABCC4 from the plasma membrane, increased drug sensitivity, and abrogated MPP1-dependent hematopoietic progenitor cell replating in methylcellulose. High-throughput screening identified Antimycin A as a small molecule that disrupted the ABCC4–MPP1 protein complex and reversed drug resistance in AML cell lines and in primary patient AML cells. In all, targeting the ABCC4–MPP1 protein complex can lead to new therapies to improve treatment outcome of AML, a disease where the long-term prognosis is poor.

Date: 2017
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DOI: 10.1038/s41467-017-01678-y

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