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Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia

ABSTRACT: Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia

PROVIDER: PRJNA834427 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18968603_1.fastq.gz	Fastqsanger.gz
	SRR18968603_2.fastq.gz	Fastqsanger.gz
	SRR18968604_1.fastq.gz	Fastqsanger.gz
	SRR18968604_2.fastq.gz	Fastqsanger.gz
	SRR18968605_1.fastq.gz	Fastqsanger.gz

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Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia [ChIP-seq]

Project description:Blinatumomab is an efficacious immunotherapeutic agent in B-cell acute lymphoblastic leukemia (ALL). However, pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. CD58 expression varied across 20 ALL moleuclar subtypes, with marked downregulation linked to PAX5 P80R mutation in leukemia. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R. Without CD58 in B-ALL, blinatumomab-induced T cell activation was abolished with transcriptomic/ epigenomic reprogramming. Finally, we screened 1,639 transcription factor genes to systematically identify regulators of CD58/CD19 expression. In conclusion, we identified novel genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

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Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia [ChIP-seq]

Project description:Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia [ChIP-seq]

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Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia [ATAC-seq]

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Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

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T-cell dysfunction during blinatumomab therapy in pediatric acute lymphoblastic leukemia

Project description:Despite the high response rate to the T-cell engager blinatumomab in B-cell acute lymphoblastic leukemia (B-ALL), maintaining persistent efficacy is a challenge. Limited data from adults with relapsed B-ALL and high disease burden suggest T-cell dysfunction with continuous blinatumomab treatment contributes to loss of response; T-cell function in patients with low disease burden or pediatric B-ALL are uncharacterized. Given the recent adoption of blinatumomab in frontline post-remission pediatric B-ALL therapy and the existence of age and leukemia burden-related immune differences, a comprehensive assessment of T-cells is needed to inform optimal continuous treatment duration. Hence, we assessed T-cell function and phenotype during a 28-day continuous intravenous blinatumomab cycle in a pediatric leukemia cohort of 11 patients aged 1-21 years; 8 received blinatumomab in minimal residual disease-negative first remission. By day 14, T-cells exhibited impairments in cytotoxicity (baseline, day 14, day 28 = 72%, 56%, 54%; p = 0.008), IFN-γ production (p = 0.0004), and T-cell receptor (TCR) signaling (mTOR and MEK) that persisted through day 28. The frequency of stem cell memory T-cells declined (p = 0.0004) while those of terminally differentiated (p = 0.012) and TIM3+ (p < 0.0001) cells were elevated at day 14. T-cells at day 14 were marked by exhaustion and terminal differentiation transcriptional signatures; genes encoding inhibitory receptors and negative regulators of TCR signaling were upregulated. Overall, multimodal T-cell dysfunction occurs by day 14. These findings could inform studies to optimize cycle duration and reveal candidate targets for functional studies aimed at ameliorating T-cell dysfunction.

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