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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202083 | GEO | 2022/12/21

REPOSITORIES: GEO

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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.

2022-12-21 | GSE202082 | GEO

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

2022-12-21 | GSE202081 | GEO

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

2022-12-21 | GSE201831 | GEO

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

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

| PRJNA834427 | ENA

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]

| PRJNA834476 | ENA

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

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

| PRJNA834470 | ENA

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

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

| PRJNA833140 | ENA

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity.

Project description:TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.

| S-EPMC8021101 | biostudies-literature

Genome-Wide CRISPR-Cas9 Screen Identifies MicroRNAs That Regulate Myeloid Leukemia Cell Growth.

Project description:Mammalian microRNA expression is dysregulated in human cancer. However, the functional relevance of many microRNAs in the context of tumor biology remains unclear. Using CRISPR-Cas9 technology, we performed a global loss-of-function screen to simultaneously test the functions of individual microRNAs and protein-coding genes during the growth of a myeloid leukemia cell line. This approach identified evolutionarily conserved human microRNAs that suppress or promote cell growth, revealing that microRNAs are extensively integrated into the molecular networks that control tumor cell physiology. miR-155 was identified as a top microRNA candidate promoting cellular fitness, which we confirmed with two distinct miR-155-targeting CRISPR-Cas9 lentiviral constructs. Further, we performed anti-correlation functional profiling to predict relevant microRNA-tumor suppressor gene or microRNA-oncogene interactions in these cells. This analysis identified miR-150 targeting of p53, a connection that was experimentally validated. Taken together, our study describes a powerful genetic approach by which the function of individual microRNAs can be assessed on a global level, and its use will rapidly advance our understanding of how microRNAs contribute to human disease.

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A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia.

Project description:Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

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