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.

  • Article
  • Published:

Molecular targets for therapy

Identification of a leukemia-initiating stem cell in human mast cell leukemia

Leukemia volume 33, pages 2673–2684 (2019)Cite this article

Subjects

Abstract

Mast cell leukemia (MCL) is a highly fatal malignancy characterized by devastating expansion of immature mast cells in various organs. Although considered a stem cell disease, little is known about MCL-propagating neoplastic stem cells. We here describe that leukemic stem cells (LSCs) in MCL reside within a CD34+/CD38− fraction of the clone. Whereas highly purified CD34+/CD38─ cells engrafted NSGhSCF mice with fully manifesting MCL, no MCL was produced by CD34+/CD38+ progenitors or the bulk of KIT+/CD34− mast cells. CD34+/CD38– MCL cells invariably expressed CD13 and CD133, and often also IL-1RAP, but did not express CD25, CD26 or CLL-1. CD34+/CD38– MCL cells also displayed several surface targets, including CD33, which was homogenously expressed on MCL LSCs in all cases, and the D816V mutant form of KIT. Although CD34+/CD38− cells were resistant against single drugs, exposure to combinations of CD33-targeting and KIT-targeting drugs resulted in LSC-depletion and markedly reduced engraftment in NSGhSCF mice. Together, MCL LSCs are CD34+/CD38− cells that express distinct profiles of markers and target antigens. Characterization of MCL LSCs should facilitate their purification and should support the development of LSC-eradicating curative treatment approaches in this fatal type of leukemia.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris M-O, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013;121:1285–95.

    CAS  PubMed  Google Scholar 

  2. Travis WD, Li CY, Hoagland HC, Travis LB, Banks PM. Mast cell leukemia: report of a case and review of the literature. Mayo Clin Proc. 1986;61:957–66.

    CAS  PubMed  Google Scholar 

  3. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129:1420–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lim K-H, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113:5727–36.

    CAS  PubMed  Google Scholar 

  5. Sperr WR, Escribano L, Jordan JH, Schernthaner GH, Kundi M, Horny HP, et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res. 2001;25:529–36.

    CAS  PubMed  Google Scholar 

  6. Valent P, Akin C, Sperr WR, Escribano L, Arock M, Horny H-P, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res. 2003;27:635–41.

    CAS  PubMed  Google Scholar 

  7. Valentini CG, Rondoni M, Pogliani EM, Van Lint MT, Cattaneo C, Marbello L, et al. Mast cell leukemia: a report of ten cases. Ann Hematol. 2008;87:505–8.

    PubMed  Google Scholar 

  8. Ustun C, Reiter A, Scott BL, Nakamura R, Damaj G, Kreil S, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014;32:3264–74.

    PubMed  PubMed Central  Google Scholar 

  9. Escribano L, Orfao A, Díaz-Agustin B, Villarrubia J, Cerveró C, López A, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998;91:2731–6.

    CAS  PubMed  Google Scholar 

  10. Escribano L, Díaz-Agustín B, Bellas C, Navalón R, Nuñez R, Sperr WR, et al. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res. 2001;25:563–70.

    CAS  PubMed  Google Scholar 

  11. Sotlar K, Horny H-P, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004;28:1319–25.

    PubMed  Google Scholar 

  12. Teodosio C, García-Montero AC, Jara-Acevedo M, Sánchez-Muñoz L, Alvarez-Twose I, Núñez R, et al. Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes. J Allergy Clin Immunol. 2010;125:719–26. 726.e1–726.e4

    CAS  PubMed  Google Scholar 

  13. Sánchez-Muñoz L, Teodosio C, Morgado JMT, Perbellini O, Mayado A, Alvarez-Twose I, et al. Flow cytometry in mastocytosis: utility as a diagnostic and prognostic tool. Immunol Allergy Clin North Am. 2014;34:297–313.

    PubMed  Google Scholar 

  14. Arock M, Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol. 2010;3:497–516.

    PubMed  Google Scholar 

  15. Joris M, Georgin-Lavialle S, Chandesris M-O, Lhermitte L, Claisse J-F, Canioni D, et al. Mast cell leukaemia: c-KIT mutations are not always positive. Case Rep Hematol. 2012;2012:517546.

    PubMed  PubMed Central  Google Scholar 

  16. Mital A, Piskorz A, Lewandowski K, Wasąg B, Limon J, Hellmann A. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur J Haematol. 2011;86:531–5.

    CAS  PubMed  Google Scholar 

  17. Valent P, Blatt K, Eisenwort G, Herrmann H, Cerny-Reiterer S, Thalhammer R, et al. FLAG-induced remission in a patient with acute mast cell leukemia (MCL) exhibiting t(7;10)(q22; q26) and KIT D816H. Leuk Res Rep. 2014;3:8–13.

    PubMed  Google Scholar 

  18. Damaj G, Joris M, Chandesris O, Hanssens K, Soucie E, Canioni D, et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS ONE. 2014;9:e85362.

    PubMed  PubMed Central  Google Scholar 

  19. Hanssens K, Brenet F, Agopian J, Georgin-Lavialle S, Damaj G, Cabaret L, et al. SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes. Haematologica. 2014;99:830–5.

    PubMed  PubMed Central  Google Scholar 

  20. Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122:2460–6.

    CAS  PubMed  Google Scholar 

  21. Wilson TM, Maric I, Simakova O, Bai Y, Chan EC, Olivares N, et al. Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis. Haematologica. 2011;96:459–63.

    CAS  PubMed  Google Scholar 

  22. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    CAS  PubMed  Google Scholar 

  23. Copland M. Chronic myelogenous leukemia stem cells: what’s new? Curr Hematol Malig Rep. 2009;4:66–73.

    PubMed  Google Scholar 

  24. Eisterer W, Jiang X, Christ O, Glimm H, Lee KH, Pang E, et al. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia. 2005;19:435–41.

    CAS  PubMed  Google Scholar 

  25. Kavalerchik E, Goff D, Jamieson CHM. Chronic myeloid leukemia stem cells. J Clin Oncol. 2008;26:2911–5.

    PubMed  Google Scholar 

  26. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.

    CAS  PubMed  Google Scholar 

  27. Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer. 2012;12:133–43.

    CAS  PubMed  Google Scholar 

  28. Valent P. Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept. Curr Cancer Drug Targets. 2011;11:56–71.

    CAS  PubMed  Google Scholar 

  29. Taussig DC, Miraki-Moud F, Anjos-Afonso F, Pearce DJ, Allen K, Ridler C, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568–75.

    CAS  PubMed  Google Scholar 

  30. Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–67.

    CAS  PubMed  Google Scholar 

  31. Herrmann H, Sadovnik I, Cerny-Reiterer S, Rülicke T, Stefanzl G, Willmann M, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014;123:3951–62.

    CAS  PubMed  Google Scholar 

  32. Järås M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci USA. 2010;107:16280–5.

    PubMed  Google Scholar 

  33. van Rhenen A, van Dongen GAMS, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007;110:2659–66.

    PubMed  Google Scholar 

  34. Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2010;2:17ra9.

    PubMed  PubMed Central  Google Scholar 

  35. Fritsche-Polanz R, Fritz M, Huber A, Sotlar K, Sperr WR, Mannhalter C, et al. High frequency of concomitant mastocytosis in patients with acute myeloid leukemia exhibiting the transforming KIT mutation D816V. Mol Oncol. 2010;4:335–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Georgin-Lavialle S, Lhermitte L, Baude C, Barete S, Bruneau J, Launay J-M, et al. Blood CD34-c-Kit+cell rate correlates with aggressive forms of systemic mastocytosis and behaves like a mast cell precursor. Blood. 2011;118:5246–9.

    CAS  PubMed  Google Scholar 

  37. Nagai S, Ichikawa M, Takahashi T, Sato H, Yokota H, Oshima K, et al. The origin of neoplastic mast cells in systemic mastocytosis with AML1/ETO-positive acute myeloid leukemia. Exp Hematol. 2007;35:1747–52.

    CAS  PubMed  Google Scholar 

  38. Rottem M, Okada T, Goff JP, Metcalfe DD. Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/Fc epsilon RI- cell population. Blood. 1994;84:2489–96.

    CAS  PubMed  Google Scholar 

  39. Kent D, Copley M, Benz C, Dykstra B, Bowie M, Eaves C. Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway. Clin Cancer Res. 2008;14:1926–30.

    CAS  PubMed  Google Scholar 

  40. Takagi S, Saito Y, Hijikata A, Tanaka S, Watanabe T, Hasegawa T, et al. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood. 2012;119:2768–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S, Reiter A, et al. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol. 2014;25:1691–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Blatt K, Herrmann H, Hoermann G, Willmann M, Cerny-Reiterer S, Sadovnik I, et al. Identification of campath-1 (CD52) as novel drug target in neoplastic stem cells in 5q-patients with MDS and AML. Clin Cancer Res. 2014;20:3589–602.

    CAS  PubMed  Google Scholar 

  43. Saleh R, Wedeh G, Herrmann H, Bibi S, Cerny-Reiterer S, Sadovnik I, et al. A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection. Blood. 2014;124:111–20.

    CAS  PubMed  Google Scholar 

  44. Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115:1976–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gotlib J, Berubé C, Growney JD, Chen CC, George TI, Williams C, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865–70.

    PubMed  Google Scholar 

  46. Florian S, Sonneck K, Hauswirth AW, Krauth M-T, Schernthaner G-H, Sperr WR, et al. Detection of molecular targets on the surface of CD34+/CD38− stem cells in various myeloid malignancies. Leuk Lymphoma. 2006;47:207–22.

    CAS  PubMed  Google Scholar 

  47. Alvarez-Twose I, Martínez-Barranco P, Gotlib J, García-Montero A, Morgado JM, Jara-Acevedo M, et al. Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia. Leukemia. 2016;30:1753–6.

    CAS  PubMed  Google Scholar 

  48. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530–41.

    CAS  Google Scholar 

  49. Blatt K, Cerny-Reiterer S, Schwaab J, Sotlar K, Eisenwort G, Stefanzl G, et al. Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis. Blood. 2015;126:2832–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sotlar K, Cerny-Reiterer S, Petat-Dutter K, Hessel H, Berezowska S, Müllauer L, et al. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol. 2011;24:585–95.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Tina Bernthaler, Mathias Schneeweiss, Karin Bauer, Niklas Müller and Sabine Cerny-Reiterer for skillful technical assistance. This study was supported by the Austrian Science Fund (FWF), SFB grants F4701 and F4704, 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.

Author information

Authors and Affiliations

  1. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria

    Gregor Eisenwort, Irina Sadovnik, Katharina Blatt, Michael Willmann, Wolfgang R. Sperr, Thomas Rülicke & Peter Valent

  2. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090, Vienna, Austria

    Gregor Eisenwort, Irina Sadovnik, Alexandra Keller, Gabriele Stefanzl, Daniela Berger, Katharina Blatt, Wolfgang R. Sperr & Peter Valent

  3. Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167, Mannheim, Germany

    Juliana Schwaab, Mohamad Jawhar & Andreas Reiter

  4. Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria

    Gregor Hoermann & Martin Bilban

  5. Department for Companion Animals & Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, 1210, Vienna, Austria

    Michael Willmann

  6. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, 1210, Vienna, Austria

    Christiana Winding & Thomas Rülicke

  7. Cellular and Molecular Oncology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, 94230, Cachan, France

    Michel Arock

Authors
  1. Gregor Eisenwort
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina Sadovnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliana Schwaab
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamad Jawhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandra Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gabriele Stefanzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniela Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katharina Blatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gregor Hoermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martin Bilban
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Willmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christiana Winding
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Wolfgang R. Sperr
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michel Arock
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Thomas Rülicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Andreas Reiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter Valent
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GE and PV planned the study; GE, IS, AK, DB, KB, GS and CW performed the experiments; GE, GH, MB, MW, TR, and PV analyzed the data; JS, MJ, MW, WRS, TR, AR, MA and PV provided research materials; GE, GH, MW, MA, AR and PV wrote the manuscript.

Corresponding author

Correspondence to Peter Valent.

Ethics declarations

Conflict of interest

PV received a research grant from Novartis, from Blueprint, and from Deciphera, and received honoraria from Novartis, Celgene, Pfizer and Deciphera. PV and AR served as a Consultant in the global Novartis trial examining the effects of midostaurin in advanced SM. WRS received honoraria from Novartis and Celgene. MA received honoraria from Deciphera, Novartis and Roche Diagnostics, and a research grant from Agensys Inc., Blueprint Medicines and Deciphera. AR received a research grant from Novartis, honoraria from Novartis and BMS, and served in advisory boards organized by Deciphera, Blueprint and Baxalta/Shire. GH received honoraria from Novartis. The other authors declare that they have no conflict of interest.

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

Eisenwort, G., Sadovnik, I., Schwaab, J. et al. Identification of a leukemia-initiating stem cell in human mast cell leukemia. Leukemia 33, 2673–2684 (2019). https://doi.org/10.1038/s41375-019-0460-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0460-6

This article is cited by

Search

Advanced search

Quick links