Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sequential treatment with ruxolitinib and imetelstat effectively depletes myelofibrosis hematopoietic stem and progenitor cells

Leukemia (2026)Cite this article

Subjects

Myelofibrosis (MF) originates at the level of hematopoietic stem and progenitor cells (HSC/HPC), and, hence, the only curative approach for MF is allogeneic stem cell (SC) transplantation, but this treatment modality is available only to a minority of patients. MF SC clones not only harbor multiple genetic abnormalities but also are characterized by shortened telomeres [1, 2] and upregulated telomerase activity (TA) independent of their driver mutational status [3, 4] which permits continued proliferation despite critically shortened telomeres. These observations provide a strong rationale for telomerase inhibition as a therapeutic strategy for depleting mutated MF HSCs/HPCs, irrespective of their driver mutational status. Imetelstat is a 13-mer oligonucleotide complimentary to the template region of telomerase RNA component [5]. It is a first-in-class, direct, and competitive inhibitor of telomerase enzymatic activity approved by regulatory agencies for treatment of patients with low- to intermediate-1 risk myelodysplastic disorders with transfusion-dependent anemia. In MF patients resistant or refractory to JAK2 inhibitor therapy, imetelstat has demonstrated disease-modifying activity as evidenced by reductions in driver mutation burden and BM fibrosis improvement, which were correlated with prolonged overall survival [6, 7]. This is likely due to the ability of imetelstat to deplete MF HSCs [1].

It has been suggested that telomerase inhibitors would be best used to eliminate residual cancer cells after the administration of conventional therapies [8, 9]. Since ruxolitinib (Rux) presently is the standard of care for MF patients, we explored the optimal schedule for combination therapy of Rux with imetelstat to treat MF patients. Given distinct mechanisms of action of imetelstat and Rux and that their most common adverse events are the development of cytopenias [6, 10], we hypothesized that combining imetelstat with Rux both at lower doses might create a regimen that would be more efficacious than a single agent alone in depleting MF HSCs/HPCs while maintaining an acceptable toxicity profile. In this study, using in vitro HPC assays and in vivo MF xenograft models, we have assessed the effects of Rux and imetelstat administered alone, simultaneously or sequentially on MF HSCs/HPCs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Effects of ruxolitinib (Rux) and imetelstat (Ime) alone and in combination on normal and MF HSCs/HPCs.
Fig. 2: Sequential ruxolitinib (Rux)→imetelstat (Ime) treatment did not affect normal NRCs but depleted MF NRCs in the bone marrows (BM) of NSG mice.

References

  1. Wang X, Hu CS, Petersen B, Qiu J, Ye F, Houldsworth J, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. 2018;2:2378–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bernard L, Belisle C, Mollica L, Provost S, Roy DC, Gilliland DG, et al. Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms. Leukemia. 2009;23:287–91.

    Article  CAS  PubMed  Google Scholar 

  3. Spanoudakis E, Bazdiara I, Pantelidou D, Kotsianidis I, Papadopoulos V, Margaritis D, et al. Dynamics of telomere’s length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms. Leuk Res. 2011;35:459–64.

    Article  CAS  PubMed  Google Scholar 

  4. Ferraris AM, Mangerini R, Pujic N, Racchi O, Rapezzi D, Gallamini A, et al. High telomerase activity in granulocytes from clonal polycythemia vera and essential thrombocythemia. Blood. 2005;105:2138–40.

    Article  CAS  PubMed  Google Scholar 

  5. Herbert BS, Gellert GC, Hochreiter A, Pongracz K, Wright WE, Zielinska D, et al. Lipid modification of GRN163, an N3’->P5’ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 2005;24:5262–8.

    Article  CAS  PubMed  Google Scholar 

  6. Mascarenhas J, Komrokji RS, Palandri F, Martino B, Niederwieser D, Reiter A, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. 2021;39:2881–92.

    Article  CAS  PubMed  Google Scholar 

  7. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908–19.

    Article  CAS  PubMed  Google Scholar 

  8. Ouellette MM, Lee K. Telomerase: diagnostics, cancer therapeutics and tissue engineering. Drug Discov Today. 2001;6:1231–7.

    Article  CAS  PubMed  Google Scholar 

  9. Shay JW, Wright WE. Telomerase: a target for cancer therapeutics. Cancer Cell. 2002;2:257–65.

    Article  CAS  PubMed  Google Scholar 

  10. Thaw K, Harrison CN, Sriskandarajah P. JAK inhibitors for myelofibrosis: strengths and limitations. Curr Hematol Malig Rep. 2024;19:264–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Duarte D, Vale N. Evaluation of synergism in drug combinations and reference models for future orientations in oncology. Curr Res Pharmacol Drug Discov. 2022;3:100110.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nieborowska-Skorska M, Maifrede S, Dasgupta Y, Sullivan K, Flis S, Le BV, et al. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017;130:2848–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shin KH, Kang MK, Dicterow E, Kameta A, Baluda MA, Park NH. Introduction of human telomerase reverse transcriptase to normal human fibroblasts enhances DNA repair capacity. Clin Cancer Res. 2004;10:2551–60.

    Article  CAS  PubMed  Google Scholar 

  14. Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18:495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mascarenhas J, Otoukesh S, Bradley T, Scott BL, Yimer HA, Dougherty S, et al. Trial update from IMproveMF, an ongoing, open-label, dose-escalation and -expansion, phase 1/1B trial to evaluate the safety, pharmacokinetics, and clinical activity of the novel combination of imetelstat with ruxolitinib in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis (MF). Blood. 2024;144:998.54.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Geron Corporation and Janssen Research & Development LLC (XW) and by National Institutes of Health (NIH), National Cancer Institute awards (P01 CA108671) (RH). We would like to thank Dr. Christoph Schaniel for his critical reading of this manuscript.

Author information

Authors and Affiliations

  1. Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Xiaoli Wang, Andrew Davis, Cing Siang Hu, Sophia Jiang, John Mascarenhas & Ronald Hoffman

  2. Geron Corporation, Foster City, CA, USA

    Fei Huang

Authors
  1. Xiaoli Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Andrew Davis
    View author publications

    Search author on:PubMed Google Scholar

  3. Cing Siang Hu
    View author publications

    Search author on:PubMed Google Scholar

  4. Fei Huang
    View author publications

    Search author on:PubMed Google Scholar

  5. Sophia Jiang
    View author publications

    Search author on:PubMed Google Scholar

  6. John Mascarenhas
    View author publications

    Search author on:PubMed Google Scholar

  7. Ronald Hoffman
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Contribution: XW designed the study, performed experiments, analyzed and interpreted data, and wrote the manuscript; AD, CSH and SJ performed experiments and analyzed data; FH contributed to study design. FH and JM interpreted data and discussed results; and RH interpreted data and revised the manuscript. All authors reviewed, edited and approved the manuscript.

Corresponding authors

Correspondence to Xiaoli Wang or Ronald Hoffman.

Ethics declarations

Competing interests

FH is currently an employee of Geron Corporation. JM has received consulting/advisory fees from Abbvie, Incyte, BMS, Novartis, Sobi, Geron, Karyopharm, DISC, Sumitomo, Keros, Takeda, Merck, Pfizer, Italfarmaco, Blueprint Medicines and PharmaEssentia, and research funding from Incyte, Novartis, AbbVie, Ajax, BMS, Geron, Kartos, Karyopharm, DISC, PharmaEssentia, and Italfarmaco Spa. Other authors have nothing to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Davis, A., Hu, C.S. et al. Sequential treatment with ruxolitinib and imetelstat effectively depletes myelofibrosis hematopoietic stem and progenitor cells. Leukemia (2026). https://doi.org/10.1038/s41375-026-02871-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41375-026-02871-z

Search

Advanced search

Quick links