DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia
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.
Authors
- Wendy Stock (ORCID: https://orcid.org/0000-0002-8349-9200)
- Mignon L. Loh (ORCID: https://orcid.org/0000-0003-4099-4700)
- Takaya Moriyama (ORCID: https://orcid.org/0000-0001-8864-4174)
- Megan Walker
- Steven Mitchell Kornblau (ORCID: https://orcid.org/0000-0002-5990-9548)
- Ching‐Hon Pui (ORCID: https://orcid.org/0000-0003-0303-5658)
- Marina Konopleva (ORCID: https://orcid.org/0000-0002-9347-2212)
- William E. Evans (ORCID: https://orcid.org/0000-0002-9333-5322)
- Amit Budhraja
- Wenjian Yang (ORCID: https://orcid.org/0000-0002-7305-5649)
- Carolin S. Escherich (ORCID: https://orcid.org/0000-0002-1402-3647)
- Ernesto Díaz-Flores (ORCID: https://orcid.org/0000-0003-2406-4597)
- Joseph T. Opferman (ORCID: https://orcid.org/0000-0002-1147-5621)
- Noemi Reyes (ORCID: https://orcid.org/0000-0003-0604-2191)
- Jun Yang (ORCID: https://orcid.org/0000-0002-4233-3220)
- Maureen M. O’Brien (ORCID: https://orcid.org/0000-0002-9054-4321)
- Hiroto Inaba (ORCID: https://orcid.org/0000-0003-0605-7342)
- Elisabeth Paietta (ORCID: https://orcid.org/0000-0002-0561-5544)
- Mark Robert Litzow (ORCID: https://orcid.org/0000-0002-9816-6302)
- Sheetal Bhatara (ORCID: https://orcid.org/0009-0007-3597-6870)
- Zhenhua Li (ORCID: https://orcid.org/0000-0001-5099-1795)
- Yizhen Li (ORCID: https://orcid.org/0000-0001-8941-6691)
- Jiyang Yu (ORCID: https://orcid.org/0000-0003-1244-4429)
- Yu-Chih Hsiao
Institutions
- Seattle Children's Hospital (US)
- Albert Einstein College of Medicine (US)
- St. Jude Children's Research Hospital (US)
- Mayo Clinic (US)
- Montefiore Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- University of Washington (US)
- WinnMed (US)
- Soochow University (CN)
- University of Chicago (US)
- Children's Hospital Colorado (US)
- Seattle Children's Hospital (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Heinrich Heine University Düsseldorf (DE)
- University of Colorado Denver (US)
Publication Details
- Journal
- Blood
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1182/blood.2024026085
- Citations
- 6
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 11.27