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

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

PROVIDER: PRJNA1098763 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28621254_1.fastq.gz	Fastqsanger.gz
	SRR28621254_2.fastq.gz	Fastqsanger.gz
	SRR28621255_1.fastq.gz	Fastqsanger.gz
	SRR28621255_2.fastq.gz	Fastqsanger.gz
	SRR28621256_1.fastq.gz	Fastqsanger.gz

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

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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.

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Project description:Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is driven by genetic alterations that induce constitutive kinase signaling and is associated with chemoresistance and high relapse risk in children and adults. Preclinical studies in the most common CRLF2-rearranged/JAK pathway-activated Ph-like ALL subtype suggest incomplete oncogene addiction and partial response to tyrosine kinase inhibitor (TKI)-based therapies, highlighting a need to elucidate alternative biologic dependencies and therapeutic vulnerabilities, although the ABL-class Ph-like ALL subtype may be preferentially TKI-sensitive. Using bulk and single-cell multiomics analyses, we profiled residual cells from Ph-like ALL xenograft models treated in vivo with inhibitors to identify mechanisms of potential therapeutic escape. We identified a specific MYC dependency in Ph-like ALL and defined a leukemia cell subpopulation with senescence-associated stem cell-like features regulated by AP-1 transcription factors. This dormant ALL subpopulation could be eradicated by dual pharmacologic inhibition of JAK/STAT and BCL-2, providing mechanistic rationale for alternative therapeutic approaches.

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