RUNX1 aberrations in blast-phase chronic myeloid leukaemia induce the RNA-binding protein SPATS2L, which promotes growth, survival and stress granule assembly

Palmer, D. A., Ogilvie-Park, D., Muir, A. L., Craig, R., Sevim, O. and Tonks, A. ORCID: https://orcid.org/0000-0002-6073-4976 2026. RUNX1 aberrations in blast-phase chronic myeloid leukaemia induce the RNA-binding protein SPATS2L, which promotes growth, survival and stress granule assembly. Leukemia 10.1038/s41375-026-03161-4

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Abstract

RUNX1 is a critical regulator of hematopoiesis. In CML, somatic RUNX1 mutations and RUNX1::MECOM/EVI1, are associated with TKI resistance and progression to BP-CML. To examine post-transcriptional dysregulation downstream of RUNX1 aberrations, we used orthogonal organic phase separation to characterise the RNA-binding proteome of RUNX1 deficient BP-CML cells. RUNX1 depleted BP-CML cells exhibited significant alterations to RBPs involved in stress response pathways and translation/ribosome-biogenesis. Furthermore, RUNX1 depletion or expression of RUNX1::EVI1 in BP-CML cells induced expression and RNA binding activity of SPATS2L, a component of stress granules (SG). Whilst RUNX1 depletion increased SG-assembly, SPATS2L depletion reduced SG-assembly and inhibited the growth/survival of multiple BP-CML cell lines. Homoharringtonine (HHT), used historically in TKI-resistant CML, ablated SG-assembly in BP-CML cells with RUNX1 depletion, and primary BP-CML cells with LOF/hypomorphic RUNX1 mutations were preferentially sensitised to HHT. Suppressing SPATS2L expression induced by RUNX1 depletion, reduced SG-forming capacity and increased the HHT-sensitivity of RUNX1 depleted BP-CML cells, suggesting SPATS2L contributes to therapeutic resistance in RUNX1 mutated CML. Finally, we demonstrate that SGs may contribute more widely to TKI-resistance in this setting. This study suggests that SPATS2L/SG induction could be critical to RUNX1-mutant leukemias, and, provides preliminary evidence for a mutationally-targeted approach in CML with RUNX1 aberrations.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full authors available at DOI
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0887-6924
Date of First Compliant Deposit:	13 October 2026
Date of Acceptance:	23 September 2026
Last Modified:	13 Oct 2026 10:36
URI:	https://orca.cardiff.ac.uk/id/eprint/190199

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