Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

Kan, Winnie L.; Dhagat, Urmi; Hercus, Timothy R.; Kaufmann, Kerstin B.; Nero, Tracy L.; Zeng, Andy G.X.; Toubia, John; Barry, Emma F.; Broughton, Sophie E.; Gómez, Guillermo A.; Dottore, Mara; Shing, Karen S. Cheung Tung; Thomas, Daniel; Benard, Brooks A.; Simpson, Kaylene J.; Schoof, Erwin M.; Goodall, Gregory J.; Begley, C. Glenn; Ekert, Paul; Tvorogov, Denis; D’Andrea, Richard J.; Dick, John E.; Parker, M.W.; López, Angel F.

doi:10.2139/ssrn.3707264

Cited by 1 publication

(1 citation statement)

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“…Recently, we developed a patient-derived AML model (OCI-AML22) that retains biological properties with broad clinical relevance 34 . The OCI-AML22 LSC population exhibits hallmark stemness properties that are highly prognostic across diverse independent cohorts of AML patient samples 1,2,29–32,35–40 . This clinically-relevant model provides a powerful tool for mechanistic and functional studies to investigate LSC biology in the correct cellular context.…”

Section: Introductionmentioning

confidence: 99%

Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties

Boutzen,

Murison,

Wang

et al. 2024

Preprint

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The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient- derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential and repopulation capacity and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for further investigation of the LSC compartment in AML.

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