Biology subjects

Boutzen, H.

Publications and source records attributed to Boutzen, H..

5 recordsLinked to original sources

bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗

bioRxiv2026

Cell-state-dependent responses to PLK1 inhibition reveal a non-canonical microtubule-endolysosomal vulnerability in quiescent leukemia stem cells

Relapse in cancer is frequently driven by therapy-resistant quiescent cancer stem cells. Conventional chemotherapy has been designed to target proliferating tumor cells and is generally presumed to be ineffective against non-cycling cancer stem cells. Using acute myeloid leukemia (AML) as a model, we challenge this prevailing view by showing that inhibition of the mitotic master regulator Polo-like kinase 1 (PLK1), a kinase extensively pursued for antiproliferative cancer therapy, unexpectedly eradicates quiescent leukemia stem cells (LSC) through a mechanism distinct from its canonical mitotic function. In proliferating AML cells, PLK1 inhibition (PLK1i) induced G2/M arrest and mitotic catastrophe. In contrast, quiescent LSC underwent apoptosis independent of mitotic arrest, revealing a cell-state-dependent mode of drug action. Mechanistically, PLK1i initiated a multi-step process through disruption of a previously unrecognized, stem cell-specific interaction between PLK1 and MAP1A, resulting in perturbed vesicle trafficking and endolysosomal homeostasis characterized by altered receptor internalization, vesicle accumulation and lysosomal dysfunction, ultimately culminating in apoptotic cell death. Combinatorial pharmacologic perturbation studies established microtubule regulation as a critical determinant of quiescent LSC survival, while ex vivo and in vivo assays demonstrated depletion of functionally-defined LSC following PLK1i. These findings identify a previously unrecognized role for PLK1 in intracellular trafficking and establish MAP1A-dependent control of vesicle homeostasis as a mechanistic determinant of cancer stem cell survival. More broadly, this study demonstrates that classical antimitotic compounds, including microtubule-targeting agents and PLK1 inhibitors, can eradicate both cycling leukemic blasts and quiescent LSC through distinct, cell state-dependent mechanisms, challenging proliferation-centric models of chemotherapy action.

cancer biology↗

bioRxiv2025

Stress Granules Underlie Acute Myeloid Leukemia Stem Cell Survival and Stress Adaptation

The link between cancer maintenance and an ability to sustain continued growth through stresses conferred by the cancer state itself is growing. However, there are significant gaps in our understanding of how this stress is managed, particularly at the level of cancer initiating cells. Here, we identify proteins comprising the dynamic, stress-adaptive ribonucleoprotein complexes known as stress granules (SG) to be enriched among the factors essential for leukemic stem cell (LSC)-driven leukemic propagation. Focusing on core SG nucleator G3BP1, we dissect the role of SGs in human acute myeloid leukemia (AML), their targetability, and the mechanisms they govern to uncover a novel propensity for AML, and in particular LSC-enriched fractions, to prime the expression of SG components, form SGs with greater fidelity and to be reliant on their establishment and continued integrity for LSC maintenance. We further unveil the transcript and protein interactome of G3BP1 in the AML context and show that consolidated control of innate immune signaling, and apoptosis repression is executed through regional binding specificity of G3BP1 to highly structured 3UTRs and cooperation with the RNA helicase UPF1 to mediate transcript decay in SGs. Altogether our findings advance novel fundamental principles of stress adaptation exploited in AML and LSCs that may extend to other cancers and uncover SGs as a novel axis for therapy development.

cancer biology↗

bioRxiv2024

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

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.

cancer biology↗

bioRxiv2022

A primary patient-derived model for investigating functional heterogeneity within the human Leukemic Stem Cell Compartment

The ability of leukemic stem cells (LSC) to evade therapy and fuel leukemic progression causing relapse impedes therapeutic success in acute myeloid leukemia (AML). The LSC pool within a patient sample is not homogenous but comprises distinct LSC subsets that vary in self-renewal and propagation properties. The stemness programs that underlie LSC types are poorly understood since human LSC studies require primary patient samples where LSC numbers are low and isolation methods impure. To overcome these challenges, we developed a patient-derived AML model system (OCI-AML22) displaying a functionally, transcriptionally and epigenetically defined cellular hierarchy driven by functional LSCs that can be immunophenotypically identified and isolated. Through single cell and functional approaches, the OCI-AML22 LSC fraction was found to contain distinct LSCs that vary in proliferative and differentiation properties. OCI-AML22 represents a valuable resource to decipher mechanisms driving stemness and the multiple layers of heterogeneity within LSCs.

cancer biology↗