DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia
Abstract
Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.
Article Details
Authors (24)
Carolin S. Escherich
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
Takaya Moriyama
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
Zhenhua Li
State Key Laboratory of Forage Breeding-by-Design and Utilization, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences
Yu-Chih Hsiao
Wenjian Yang
Yizhen Li
Noemi Reyes
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
Megan Walker
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
Amit Budhraja
5Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN
Sheetal Bhatara
5Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN
Ernesto Diaz-Flores
2Inograft Biotherapeutic Inc., Palo Alto, United States
Wendy Stock
Elisabeth Paietta
4Montefiore Medical Center, Moses Campus, Bronx, United States
Marina Y. Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center
Steven M. Kornblau
8Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Mark R. Litzow
Mayo Clinic
Hiroto Inaba
Ching-Hon Pui
Joseph T. Opferman
5Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN
Mignon L. Loh
Seattle Children’s Hospital, Seattle
Jiyang Yu
Department of Chemistry, Advanced Institute of Future Energy, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Porous Materials for Separation and Conversion
Maureen M. O’Brien
Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora
William E. Evans
Jun J. Yang
Department of Pharmacy and Pharmaceutical Sciences