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 to the Editor
  • Published:

Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor β chain and KIT V654A

Leukemia volume 26, pages 1422–1425 (2012)Cite this article

Mast cells exit the bone marrow as immature multilineage cells that circulate in the blood and subsequently undergo full differentiation upon reaching a target organ (reviewed in Gilfillan and Tkaczyk1). Unlike other hematopoietic cells, differentiated mast cells continue to express KIT, a transmembrane receptor with a bipartite intracellular kinase domain.1 The main ligand of KIT is stem cell factor (also known as KIT ligand), which stimulates mast-cell survival, development, maturation and activation.1 Mast cells also express a high-affinity cell-surface IgE receptor, FcɛRI, which recognizes the Fc portion of IgE and is required for mast-cell survival via signaling through LYN and SYK kinases.1

Mast-cell leukemia (MCL) is an aggressive form of systemic mastocytosis characterized by the overproliferation of atypical mast cells, promastocytes and blasts that produce, among other substances, tryptase.2 MCL is often linked to somatically acquired activating mutations in the KIT receptor that result in uncontrolled ligand-independent signaling by KIT and hyperproliferation of mast cells (reviewed in Ustun et al.3). The KIT D816V mutation causes resistance to imatinib therapy.3 Mutations in TET2 and NRAS have also been described in mastocytosis patients and each of them segregates with the KIT D816V mutation,4, 5 suggesting that more than one lesion is required to drive leukemogenesis. In order to identify novel MCL determinants, we utilized two approaches to undertake the first comprehensive study of the DNA changes in an MCL patient. This study was approved by the Institutional Review Boards of the North Shore-LIJ Health System and the Cold Spring Harbor Laboratory. The patient gave written informed consent in accordance with the Declaration of Helsinki.

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

Relevant articles

Open Access articles citing this article.

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

Figure 1

References

  1. Gilfillan AM, Tkaczyk C . Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 2006; 6: 218–230.

    Article  CAS  PubMed  Google Scholar 

  2. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001; 25: 603–625.

    Article  CAS  Google Scholar 

  3. Ustun C, Deremer DL, Akin C . Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. Leuk Res 2011; 35: 1143–1152.

    Article  CAS  PubMed  Google Scholar 

  4. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009; 23: 900–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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: 459–463.

    Article  CAS  PubMed  Google Scholar 

  6. Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz Jr LA, Sjoblom T et al. The colorectal microRNAome. Proc Natl Acad Sci USA 2006; 103: 3687–3692.

    Article  CAS  Google Scholar 

  7. Piriyapongsa J, Jordan IK . A family of human microRNA genes from miniature inverted-repeat transposable elements. PLoS One 2007; 2: e203.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hartmann K, Wardelmann E, Ma Y, Merkelbach-Bruse S, Preussner LM, Woolery C et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology 2005; 129: 1042–1046.

    Article  CAS  PubMed  Google Scholar 

  9. Roberts KG, Odell AF, Byrnes EM, Baleato RM, Griffith R, Lyons AB et al. Resistance to c-KIT kinase inhibitors conferred by V654A mutation. Mol Cancer Ther 2007; 6: 1159–1166.

    Article  CAS  PubMed  Google Scholar 

  10. Kraft S, Kinet JP . New developments in FcɛRI regulation, function and inhibition. Nat Rev Immunol 2007; 7: 365–378.

    Article  CAS  PubMed  Google Scholar 

  11. Donnadieu E, Jouvin MH, Rana S, Moffatt MF, Mockford EH, Cookson WO et al. Competing functions encoded in the allergy-associated FcɛRIbeta gene. Immunity 2003; 18: 665–674.

    Article  CAS  PubMed  Google Scholar 

  12. Cruse G, Kaur D, Leyland M, Bradding P . A novel FcɛRIbeta-chain truncation regulates human mast cell proliferation and survival. FASEB J 2010; 24: 4047–4057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 2009; 36: 326–339.

    Article  CAS  PubMed  Google Scholar 

  14. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, LaCasce A et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 2578–2585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hahn CK, Berchuck JE, Ross KN, Kakoza RM, Clauser K, Schinzel AC et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 2009; 16: 281–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was funded by The Don Monti Memorial Research Foundation (SLA and SWL) and by The Ryan Gibson Foundation (MSS). SWL is a Howard Hughes Medical Institute Investigator. We gratefully acknowledge Dr W Richard McCombie for guidance with sequencing, Dr Shiroo Parshad for assistance with patient medical care, Dr Judith Brody for bone marrow interpretation, Dr Saul Teichberg for electron microscopy, Dr Piers Patten for scientific discussion, Candace Schiffer and Erin Boyle for patient sample collection and the members of the Laboratory of Experimental Immunology of the Feinstein Institute for Medical Research for their assistance in cryopreserving cells. Drs Chris Vakoc, Iris Applemann and Zhen Zhao are thanked for their critical reading of the manuscript.

Author information

Author notes

  1. S W Lowe

    Present address: 4Current address: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    M S Spector, I Iossifov, C He & S W Lowe

  2. Department of Medicine, North Shore University Hospital-Long Island Jewish Medical Center, Lake Success, NY, USA

    A Kritharis, J E Kolitz & S L Allen

  3. Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA

    A Kritharis, J E Kolitz & S L Allen

Authors
  1. M S Spector
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Iossifov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Kritharis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J E Kolitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S W Lowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S L Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S W Lowe.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spector, M., Iossifov, I., Kritharis, A. et al. Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor β chain and KIT V654A. Leukemia 26, 1422–1425 (2012). https://doi.org/10.1038/leu.2011.354

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.354

This article is cited by

Search

Advanced search

Quick links