An unexpected protein interaction promotes drug resistance in leukemia.

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.

• Authors: 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, John D Schuetz
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1547 (11 16 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29146910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ABCC4 protein, human
• Blood Proteins
• MPP1 protein, human
• Membrane Proteins
• Multidrug Resistance-Associated Proteins
• Antimycin A

Topics

• Acute Disease
• Animals
• Antimycin A (pharmacology)
• Blood Proteins (genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• HEK293 Cells
• Hematopoietic Stem Cells (metabolism)
• Humans
• Kaplan-Meier Estimate
• Leukemia, Myeloid (genetics, metabolism, pathology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Protein Binding (drug effects)