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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia

Leukemia volume 35, pages 3176–3187 (2021)Cite this article

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Abstract

Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38− fraction of the malignant clone. Whereas CD34+/CD38− cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34− monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38− cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.

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Fig. 1: CD34+ cells from CMML or sAML donors engraft in NSGS mice.
Fig. 2: Differential engraftment of CD38+ cells in CMML and sAML.
Fig. 3: Expression of selected markers on the surface of CMML- and sAML-LSC.
Fig. 4: Upregulation of cell surface markers on LSC during progression to sAML.
Fig. 5: Effect of GO and venetoclax on CMML LSC proliferation and engraftment.

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Acknowledgements

We like to thank Christiana Winding, Tina Bernthaler, and Siegfried Kosik for skillful technical assistance. This study was supported by the Austrian Science Fund (FWF), grants F4704-B20, P30625-B28, and a Research Grant of the Medical University of Vienna, Austria. Cell sorting experiments were performed with support from the Core Facility Flow Cytometry, Medical University of Vienna.

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Author notes

  1. These authors contributed equally: Gregor Eisenwort, Irina Sadovnik.

Authors and Affiliations

  1. Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    Gregor Eisenwort, Irina Sadovnik, Alexandra Keller, Daniel Ivanov, Barbara Peter, Daniela Berger, Gabriele Stefanzl, Karin Bauer, Karoline V. Gleixner, Wolfgang R. Sperr & Peter Valent

  2. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria

    Gregor Eisenwort, Irina Sadovnik, Barbara Peter, Daniela Berger, Gabriele Stefanzl, Karin Bauer, Katharina Slavnitsch, Georg Greiner, Karoline V. Gleixner, Wolfgang R. Sperr, Michael Willmann, Thomas Rülicke & Peter Valent

  3. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria

    Katharina Slavnitsch & Thomas Rülicke

  4. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Georg Greiner

  5. Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria

    Georg Greiner

  6. Department for Companion Animals and Horses, Clinic for Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria

    Michael Willmann

  7. Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria

    Heinz Sill

  8. Elisabethinen Hospital Linz, Linz, Austria

    Peter Bettelheim

  9. Medical School, Sigmund Freud University, Vienna, Austria

    Klaus Geissler

  10. Division of Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    Michael Deininger

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  1. Gregor Eisenwort
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Contributions

GE, IS, and PV designed the study, analyzed the data and wrote the manuscript. GE, BP, IS, AK, DI, KB, DB, and GS performed key laboratory experiments. PB, HS, KG, KVG, WRS, and MD provided patients’ samples and clinical information. GG performed and analyzed molecular studies. MW, KS and TR performed animal experiments. All authors wrote parts of the manuscript, corrected the draft version of the manuscript and approved the final version of the document.

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Correspondence to Peter Valent.

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Conflict of interest

PV received honoraria from Pfizer. HS received honoraria from Pfizer and AbbVie. MD received honoraria from Pfizer and Incyte. The other authors declare no conflict of interest.

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Eisenwort, G., Sadovnik, I., Keller, A. et al. Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia. Leukemia 35, 3176–3187 (2021). https://doi.org/10.1038/s41375-021-01227-z

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