Poster Presentation 35th Lorne Cancer Conference 2023

Targeting RNA-binding protein, NUDT21, enhances CD19 abundance on human B-cell acute lymphoblastic leukaemia cells (#353)

Matthew T Witkowski 1 , Soobeom Lee 2 , Eric Wang 3 , Anna K Lee 2 , Alexis Talbot 4 , Chao Ma 5 , Nikolaos Tsopoulidis 6 , Justin Brumbaugh 7 , Yaqi Zhao 8 , Kathryn G Roberts 8 , Simon J Hogg 3 , Sofia Nomikou 2 , Yohana E Ghebrechristos 2 , Palaniraja Thandapani 2 , Charles G Mullighan 8 , Konrad Hochedlinger 6 , Weiqiang Chen 5 , Omar Abdel-Wahab 3 , Justin Eyquem 4 , Iannis Aifantis 2
  1. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  2. Pathology, NYU School of Medicine, New York, NY, USA
  3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  4. Department of Medicine, University of California San Francisco, San Francisco, California, USA
  5. Department of Mechanical and Aerospace Engineering, NYU, New York, NY, USA
  6. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts , USA
  7. Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA
  8. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

B cell progenitor acute lymphoblastic leukaemia (BCP-ALL) treatment has been revolutionized by T cell-based immunotherapies - including chimeric antigen receptor (CAR) T cell therapy and bi-specific T cell engager therapeutic, blinatumomab - targeting surface glycoprotein CD19. Unfortunately, many B-ALL patients will fail immunotherapy due to ‘antigen escape’ – the loss or absence of leukaemic CD19 targeted by anti-leukaemic T cells. Here, we utilized genome-wide CRISPR/Cas9 screening approach to identify modulators of CD19 abundance on human BCP-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 mRNA polyadenylation and stability. NUDT21 deletion in BCP-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human BCP-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify novel CD19 modulators in human BCP-ALL.