RUNX1 aberrations in blast-phase chronic myeloid leukaemia induce the RNA-binding protein SPATS2L, which promotes growth, survival and stress granule assembly
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.
Authors
- Faraz K. Mardakheh (ORCID: https://orcid.org/0000-0003-3896-0827)
- Satu M. Mustjoki (ORCID: https://orcid.org/0000-0002-0816-8241)
- David A. Palmer (ORCID: https://orcid.org/0000-0003-0884-995X)
- Philip A. Lewis (ORCID: https://orcid.org/0000-0002-2868-2459)
- Gillian A. Horne (ORCID: https://orcid.org/0000-0001-9741-7352)
- Kimmo Porkka (ORCID: https://orcid.org/0000-0003-4112-5902)
- Mhairi Copland (ORCID: https://orcid.org/0000-0002-7655-016X)
- Kate J. Heesom (ORCID: https://orcid.org/0000-0002-5418-5392)
- Sophie G. Kellaway (ORCID: https://orcid.org/0000-0002-4011-7460)
- Michelle J. West (ORCID: https://orcid.org/0000-0002-9497-9365)
- Benjamin P. Towler (ORCID: https://orcid.org/0000-0001-7884-1131)
- Shady Adnan Awad (ORCID: https://orcid.org/0000-0001-6205-7799)
- Timothy J. T. Chevassut (ORCID: https://orcid.org/0000-0001-8672-1906)
- Gareth Morgan (ORCID: https://orcid.org/0000-0003-0429-6294)
- Marieangela C. Wilson (ORCID: https://orcid.org/0000-0001-6218-3533)
- Lauren Stott (ORCID: https://orcid.org/0009-0005-9400-6642)
- N. Bayat
- A. L. Muir
- D. Ogilvie-Park (ORCID: https://orcid.org/0009-0009-0554-4625)
- O. Sevim
- D. Famili
- S. Jain
- H. Webb
- A. Tonks
- R. Craig
- A. Kakkar (ORCID: https://orcid.org/0009-0002-8134-371X)
Institutions
- Brighton and Sussex Medical School (GB)
- University of Helsinki (FI)
- University of Nottingham (GB)
- Cairo University (EG)
- University of Sussex (GB)
- Queen Mary University of London (GB)
- Helsinki University Hospital (FI)
- University of Bristol (GB)
- University of Oxford (GB)
- NIHR Oxford Musculoskeletal Biomedical Research Centre (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Cancer Society of Finland (FI)
- University Hospitals Sussex NHS Foundation Trust (GB)
- MRC Molecular Haematology Unit
- Pamukkale University (TR)
- University of Glasgow (GB)
- Cardiff University (GB)
Publication Details
- Journal
- Leukemia
- Published
- 2026-10-09
- DOI
- https://doi.org/10.1038/s41375-026-03161-4
- Primary Topic
- Chronic Myeloid Leukemia Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00