A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth
- 1Imperial College London
Abstract
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.
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BibTeX
@misc{pospori2026combined,
title = {{A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth}},
author = {C. Pospori and A. Donada and H. Boutzen and W. Grey and N. Rabas and N. Kassara and W. Sun and F. Birch and C. Georgiou and S. Gibson and A. A. Yong and A. Karoutas and T. Rizou and D. Vassiliadis and G. Stevens and T. J. Williams and R. Khorshed and M. Haltalli and A. Murison and M.-N. Skoufou and K. Sloan and H. Encabo and J. Hopkins and C. Christodoulidou and I. Rondriguez-Hernandez and P. Chakravarty and D. Stampoulis and S. Atkinson and F. Hearn-Yeates and K. Polizou and E. Trompouki and R. Burt and A. Innes and H. Stauss and R. Chakraverty and S. Z. Xie and M. Dawson and J. Dick and I. Malanchi and D. Bonnet and C. Lo Celso},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.750099},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750099v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth
AU - C. Pospori
AU - A. Donada
AU - H. Boutzen
AU - W. Grey
AU - N. Rabas
AU - N. Kassara
AU - W. Sun
AU - F. Birch
AU - C. Georgiou
AU - S. Gibson
AU - A. A. Yong
AU - A. Karoutas
AU - T. Rizou
AU - D. Vassiliadis
AU - G. Stevens
AU - T. J. Williams
AU - R. Khorshed
AU - M. Haltalli
AU - A. Murison
AU - M.-N. Skoufou
AU - K. Sloan
AU - H. Encabo
AU - J. Hopkins
AU - C. Christodoulidou
AU - I. Rondriguez-Hernandez
AU - P. Chakravarty
AU - D. Stampoulis
AU - S. Atkinson
AU - F. Hearn-Yeates
AU - K. Polizou
AU - E. Trompouki
AU - R. Burt
AU - A. Innes
AU - H. Stauss
AU - R. Chakraverty
AU - S. Z. Xie
AU - M. Dawson
AU - J. Dick
AU - I. Malanchi
AU - D. Bonnet
AU - C. Lo Celso
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.750099
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.750099v1
AB - 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.
ER -