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Targeting Senescent Stem-Like Subpopulations in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Donggeun Lee

LAB HEAD: Junmin Peng

PROVIDER: PXD053611 | Pride | 2025-01-28

REPOSITORIES: pride

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			Action	DRS
	Fe_1st_1_2.1.pepXML	Pepxml
	Fe_1st_1_2.mzXML	Mzxml
	Fe_1st_1_2.raw	Raw
	Fe_1st_2_2.1.pepXML	Pepxml
	Fe_1st_2_2.mzXML	Mzxml

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