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Genome-wide CRISPR Screen Identifies DNTT as a Key Regulator of Inotuzumab Ozogamicin Response in B-cell Acute Lymphoblastic Leukemia

ABSTRACT: Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a top driver of InO resistance. Our results directly show the effects of DNTT expression on H2AX phosphorylation, DNA damage response signaling, cell cycle arrest and mitochondrial apoptotic priming, ultimately conferring leukemia resistance to InO. Screening 196 primary human B-ALL samples for InO sensitivity confirmed the impact of DNTT expression on InO response. Additionally, low DNTT expression was found in the residual leukemia blasts post InO treatment in patients enrolled in the COG trial AALL1621. Collectively, we demonstrate that loss of DNTT diminishes B-ALL sensitivity to InO in vitro and promotes leukemia cell survival during InO treatment in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264338 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF within 42 patient samples obtained from COG 8704 and, using PAM to define a smaller classifier for the U133A chip, correctly identified the single IF case and patients with persistently circulating blasts. Genetic profiling may identify T-ALL patients who are likely to fail induction and for whom alternate treatment strategies might be beneficial. This SuperSeries is composed of the following subset Series:; GSE14613: Microarray analyses of induction failure in T-ALL (COG study 8704); GSE14615: Microarray analyses of induction failure in T-ALL (COG study 9404) Experiment Overall Design: Refer to individual Series Experiment Overall Design: This was a case-controlled, retrospectively designed study. We performed expression profiles on 92 patients with T-ALL treated on Children's Oncology Group studies 8704 (42 patients) and 9404 (50 patients). Experiment Overall Design: Expression profiles were obtained from patients with newly diagnosed T-ALL. NR = no response (induction failure); F= failure (relapse); C= Complete Continous Remission.

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Genome-wide CRISPR Screen Identifies DNTT as a Key Regulator of Inotuzumab Ozogamicin Response in B-cell Acute Lymphoblastic Leukemia

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