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Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scATAC-seq]

ABSTRACT: Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scATAC-seq]

PROVIDER: PRJNA1098761 | ENA |

REPOSITORIES: ENA

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Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scATAC-seq]

Project description:Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a common high-risk leukemia subtype defined by a kinase-activated gene expression pattern and chemoresistance, with low overall survival rates in both children and adults. Clinical responses of patients with Ph-like ALL to tyrosine kinase inhibitor (TKI)-based therapies are incomplete, suggesting partial oncogene addiction and highlighting the need to elucidate alternative biologic dependencies to cure patients. Herein, we report integrated bulk and single-cell multiomics studies of Ph-like ALL cells treated in vitro and in vivo with targeted agents to comprehensively define signaling adaptations and resistant subpopulations. Characterizing residual/resistant human ALL cells harvested from murine spleens revealed transcriptional regulatory network changes and kinase signaling adaptations. We identified key transcription factors including c-MYC and AP1 that mediate transcriptional rewiring associated with therapeutic escape, and demonstrate a specific MYC dependency in Ph-like ALL cells. We found a sub-population of leukemia blasts that have high senescence-associated stem cell-like features that is effectively eradicated only with combined STAT and BCL-2 inhibition. This is clinically significant since both conventional chemotherapy and ruxolitinib are ineffective against senescent stem-like blasts, which may mediate therapeutic tolerance and repopulate relapse. Our findings demonstrate that systems level discovery of key oncogenic dependencies and escape pathways can be exploited for co-targeting or sequential treatment to optimally eradicate blasts and cure this high-risk leukemia subtype.

2025-01-09 | GSE263708 | GEO

Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scRNA-seq]

Project description:Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scRNA-seq]

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Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk ATAC-seq]

Project description:Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk ATAC-seq]

| PRJNA1098763 | ENA

Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk RNA-seq]

Project description:Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk RNA-seq]

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Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [scRNA-seq]

2025-01-09 | GSE263707 | GEO

Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk ATAC-seq]

2025-01-09 | GSE263710 | GEO

Targeting signaling rewiring and resistant subpopulations in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia [Bulk RNA-seq]

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Effect of imatinib on philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.

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Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL)

Project description:Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL)

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Effect of imatinib on philadelphia chromosome positive acute lymphoblastic leukemia

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